Conditions: Recurrent B-Cell Non-Hodgkin Lymphoma Recurrent Chronic Lymphocytic Leukemia Recurrent Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Lymphoplasmacytic Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Nodal Marginal Zone Lymphoma Recurrent Small Lymphocytic Lymphoma Recurrent Splenic Marginal Zone Lymphoma Recurrent Waldenstrom Macroglobulinemia Refractory B-Cell Non-Hodgkin Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue Refractory Follicular Lymphoma Refractory Lymphoplasmacytic Lymphoma Refractory Nodal Marginal Zone Lymphoma Refractory Small Lymphocytic Lymphoma Refractory Splenic Marginal Zone Lymphoma Refractory Waldenstrom Macroglobulinemia Richter Syndrome Waldenstrom Macroglobulinemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 65
Healthy volunteers: no

Brief summary:
This phase II trial studies how well pembrolizumab alone or with idelalisib or ibrutinib works in treating patients with chronic lymphocytic leukemia or other low-grade B-cell non-Hodgkin lymphomas that have returned after a period of improvement (relapsed) or have not responded to treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Idelalisib and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab alone or with idelalisib or ibrutinib may be an effective treatment in patients with chronic lymphocytic leukemia or other low-grade B-cell non-Hodgkin lymphomas.

Detailed description:
PRIMARY OBJECTIVE:

I. Test the efficacy (overall response rate) of single-agent MK-3475 (pembrolizumab) in relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (Arm A) other low grade B-cell non-Hodgkin lymphoma (B-NHL), and CLL with Richter's transformation (Arm C).

SECONDARY OBJECTIVES:

I. Test the safety of single-agent MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C).

II. Test the overall survival, progression free survival, treatment free survival, duration of response and time to next therapy of single-agent MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C).

III. Test the complete response rate of single MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C).

IV. Test the safety of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C).

V. Test the progression-free survival, treatment-free survival, duration of response and time to next therapy, as well as overall survival of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C).

VI. Test the overall and complete response rates of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C).

CORRELATIVE RESEARCH OBJECTIVES:

I. To assess the potential association between programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1)/PD-L2 expression on tumor and T cells and/or PD-L1 soluble levels in plasma with clinical efficacy of PD-1 blockade.

II. To investigate the effects of MK-3475 on selected markers of immune modulation and immune profiles in peripheral blood and tumor samples.

III. Examine T-cell immune synapse function and expression/location of co-stimulatory and co-inhibitory molecules (including effector molecules) as potential biomarkers to response for anti-PD-1 immune checkpoint blockade immunotherapy.

OUTLINE:

ALL PATIENTS (ARMS A, B, and C): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. Patients with CLL or CLL with Richter's transformation experiencing stable disease without partial remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the treatment continuation phase.

CONTINUATION PHASE (ARMS A and C): Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib orally (PO) twice daily (BID) on days 1-21 OR ibrutinib PO once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Arms:
arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. Patients with CLL or CLL with Richter's transformation experiencing stable disease without partial remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the treatment continuation phase.

CONTINUATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib PO BID on days 1-21 OR ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator.

Interventions: intervention 1: Ibrutinib intervention 2: Idelalisib intervention 3: Laboratory Biomarker Analysis intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Given IV

Protocol document:
Prot_SAP_000.pdf: 


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Table of Contents 
A Phase II Study of Anti-PD-1 Antibody (MK-3475) in Relapsed/Refractory Chronic Lymphocytic 
Leukemia (CLL) and Other Low Grade B Cell Non-Hodgkin Lymphoma (NHL) ...................................... 1 
Protocol Resources ........................................................................................................................................ 3 
Table of Contents .......................................................................................................................................... 4 
Schema for CLL (Arm A) 5 ........................................................................................................................... 5 
Schema for B-NHL (Arm B) ........................................................................................................................ 7 
Schema for CLL with Richter’s transformation (Arm C) ............................................................................. 9 
1.0 
Background ................................................................................................................................. 11 
2.0 
Goals ........................................................................................................................................... 18 
3.0 
Patient Eligibility ........................................................................................................................ 20 
4.0 
Test Schedule .............................................................................................................................. 26 
5.0 
Grouping Factor: ......................................................................................................................... 33 
6.0  
Registration Procedures .............................................................................................................. 33 
7.0 
Protocol Treatment ...................................................................................................................... 35 
8.0 
Dose modification based on Adverse Events .............................................................................. 38 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 46 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................................... 51 
11.0 
Treatment Evaluation .................................................................................................................. 58 
12.0 
Descriptive Factors ..................................................................................................................... 75 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 75 
14.0 
Body Fluid Biospecimens ........................................................................................................... 78 
15.0 
Drug Information ........................................................................................................................ 83 
16.0 
Statistical Considerations and Methodology ............................................................................... 94 
17.0 
Pathology Considerations/Tissue Biospecimens: ..................................................................... 102 
18.0 
Records and Data Collection Procedures .................................................................................. 105 
19.0  
Budget ....................................................................................................................................... 108 
20.0 
References ................................................................................................................................. 109 
Appendix I  NYHA Classification ............................................................................................................ 111 
Appendix II  Rai Classification ................................................................................................................. 112 
Appendix III  ECOG Performance Status Scale ....................................................................................... 113 
Appendix IV  Grading Scale for Hematologic Toxicity in CLL Studies1................................................. 114 
Appendix V  Specimen Checklist and Shipping Instructions ................................................................... 115 
Appendix VI  Ibrutinib/Idelalsib Medication Diary.................................................................................. 118 
Appendix VII   Inhibitors of CYP3A4/5 ................................................................................................... 119 
 


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Protocol Version:  October 1, 2020  
 
Schema for CLL (Arm A) 5 
Arm A is closed for accrual in April, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cycle length = 21 days 
Registration 
PD at any time 
Unacceptable adverse event                  Event Monitoring 
during cycle 1  
 
Patient refusal  
 
Arm A: 
MK-3475 200mg IV 
Day 1 each cycle 
PR/CR 
Continue MK-3475 200mg IV 
Day 1 each cycle 
up to 12 months 1, 3 
Response Evaluation at  
3 months (or earlier time 
point) 
PD or SD at 3 month 
PD at any time 
Continuation Phase: Has patient had Ibrutinib?6 
yes 
no 
Idelalisib4 
150 mg orally twice daily 
Each cycle up to 12 month1,3 
Ibrutinib4 
420 mg orally once daily 
Each cycle up to 12 month1,3 
Observation2 
Event Monitoring 
Observation2 
Event Monitoring 


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1 Total duration of treatment including both single-agent or combination therapy combined is a maximum 
of 24 months.  NOTE: If patient is continuing to benefit from treatment after 12 months, they may 
continue to receive treatment up to a total duration of 24 months including both single-agent and 
combination therapy at investigator/sponsor discretion. 
2Q 3 months x 4 
3If CLL patients have achieved MRD negative CR/CRi confirmed by bone marrow or PET/CT 
evaluation, patients could continue the treatment for 2 more cycles and stop the treatment at the discretion 
of the treating provider and enter observation. 
4Signal inhibitor can be continued or stopped at the end of therapy (12 or 24 months) per treating 
physician discretion. 
5Including CLL patients with Richter’s transformation or Hodgkin’s transformation for Arm A.  As per 
MCCC Addendum 2: An arm (Arm C) with CLL patients with Richter’s transformation only is added to 
the study.  
6Disease measurements and lab parameters obtained after the last cycle of single-agent therapy are set as 
the baseline measurements/labs for the continuation phase. 




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Availability: Commercially supplied 
Generic name:  Idelalisib 
Brand name(s): Zydelig® 
Mayo Abbreviation:  IDELALISIB  
Availability: Commercially supplied 
 


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Schema for CLL with Richter’s transformation (Arm C)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cycle length = 21 days 
Registration 
PMD or PD  
during Continuation Phase 
Unacceptable adverse event                  Event Monitoring 
during Cycle 1  
 
Patient refusal  
 
Arm C: 
MK-3475 200mg IV  
Day 1 each cycle  
PMR/CMR 
Continue MK-3475 200mg IV 
Day 1 each cycle  
up to 12 months 1, 3 
Response Evaluation at  
3 months (or earlier time point) 
PMD or PD or NMR or 
SD at 3 month 
PMD or PD at any 
time 
Continuation Phase: Has patient had 
Ibrutinib?5 
yes 
no 
Idelalisib4 
150 mg orally twice daily 
Each cycle up to 12 month1,3 
Ibrutinib4 
420 mg orally once daily 
Each cycle up to 12 month1,3 
Observation2 
Event Monitoring 
Observation2 
Event Monitoring 


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1 Total duration of treatment including both single-agent or combination therapy combined is a maximum 
of 24 months.  NOTE: If patient is continuing to benefit from treatment after 12 months, they may 
continue to receive treatment up to a total duration of 24 months including both single-agent and 
combination therapy at investigator/sponsor discretion. 
2Q 3 months x 4 
3If CLL with Richter’s transformation patients have achieved CMR (complete metabolic response) 
confirmed by bone marrow and PET/CT evaluation, patients could continue the treatment for 2 more 
cycles and stop the treatment at the discretion of the treating provider and enter observation. 
4Signal inhibitor can be continued or stopped at the end of therapy (12 or 24 months) per treating 
physician discretion. 
5 Disease measurements and lab parameters obtained after the last cycle of single-agent therapy are set as        
the baseline measurements/labs for the continuation phase. 
 


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1.0 
Background 
1.1 
Overview of Chronic Lymphocytic Leukemia (CLL) 
Approximately 16,000 new CLL cases are diagnosed annually and ~100,000 patients are 
currently alive with CLL disease in the United States. Approximately 70% CLL patients 
eventually progress to require treatment and a majority of these patients will ultimately 
die from CLL or CLL related complications. Except limited patients who underwent 
allogeneic stem cell transplant and achieved long term remission, CLL is an incurable 
disease. Chemoimmunotherapy (CIT), typically as a combination of a purine analog, 
cyclophosphamide and rituximab, is very effective and has been established as the front-
line therapy for CLL. However, majority of treated patients will relapse. Therapies for the 
relapsed CLL patients are evolving. Bendamustine and rituximab combination therapies 
have emerged as one of the effective approaches for relapsed patients. However, only 
about 10% of patients achieve a complete remission and around 60% overall response 
rate can be achieved with this approach. Progression free survival (PFS) is typically short 
in the range of 1-2 years (Fischer, Cramer et al. 2011).  
In the last 5 years, significant advancements have been made in the understanding of 
importance of B-cell receptor (BCR) signal pathway in CLL disease as well as in other 
B-cell lymphoma. Agents targeting BCR pathway, specifically Bruton’s Tyrosine Kinase 
(BTK) inhibitor Ibrutinib and PI3K inhibitor Idelalisib, have been observed to achieve 
approximately 70% overall response rate in relapsed/refractory CLL(Byrd, Furman et al. 
2013). Ibrutinib has been FDA approved for previous treated CLL patients. The longest 
follow-up data on Ibrutinib showed about 40-50% CLL patients relapsed after about 2.5 
to 3 years of Ibrutinib treatment. CLL relapse after Ibrutinib therapy has been observed 
and how to manage relapsed CLL patients after Ibrutinib therapy is unknown. 
1.2 
Overview of low grade non-Hodgkin Lymphoma (NHL) 
It is estimated that ~65,000 new NHL was diagnosed annually and ~ 500,000 people are 
currently living with NHL in the United States.  Low grade NHL accounts for 
approximately one third of all cases of NHL.  While introduction of CIT has improved 
therapy results both upfront and at relapse, the vast majority of patients with low grade 
NHL remains incurable and eventually will succumb to the disease. The most recent 
chemotherapeutic agent that has been approved by the Food and Drug Administration for 
use in patients with rituximab-refractory indolent non-Hodgkin's lymphoma is the 
alkylating agent bendamustine, which has become an important therapeutic option, 
although it is not curative. Bendamustine and rituximab combination achieves over 90% 
overall response and improved progression free survival compared to R-CHOP (Rummel, 
Niederle et al. 2013). Similarly rituximab maintenance after initial CIT is associated with 
improved progression free and overall survival (Hochster, Weller et al. 2009). However, 
patients continue to relapse. There is no consensus regarding the choice of salvage, 
second and subsequent chemotherapies in treatment of these lymphomas. Development 
of novel therapies for relapsed low grade NHL patients is needed. 
1.3 
Overview of PD-1 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 excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 


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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)(Talmadge, Donkor et al. 2007; Francisco, Sage et al. 2010).  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(Galon, Costes 
et al. 2006; Talmadge, Donkor et al. 2007).  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-
cells, T regs and Natural Killer cells(Kloor 2009), as well as subsets of macrophages and 
dendritic cells(Hillen, Baeten et al. 2008).  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(Hiraoka 2010).  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs.  Binding of 
either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 
is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves 
to dampen unwarranted T-cell function in peripheral tissues(Hiraoka 2010).  Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor. This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
1.31 
PD-1 is a marker of exhaustion in CLL and other B-NHL T cells 
T-cells in low-grade lymphomas as well as chronic lymphocytic leukemia (CLL) 
are dysfunctional and PD-1 expression on these cells is higher than on normal T 
cells (Ramsay, Clear et al. 2012). Blocking the interaction of PD-1 with its 
ligands can reenergize the defective CLL T cell function (Nunes, Wong et al. 
2012; Ramsay, Clear et al. 2012; Riches, Davies et al. 2013). We have shown 
that PD-1 expression is detected in follicular lymphoma (FL) T cells and its 
diffuse pattern of staining is associated with worse survival(Smeltzer, Jones et al. 
2013). PD-1 expression in FL T cells is increased when FL transformed into 
diffuse large cell lymphoma (DLBCL). In FL T cells, dim PD-1 surface 
expression represents an exhausted T cell phenotype and is associated with worse 
progression free survival (Yang, Grote et al. 2013). PD-1 expression is also 
detected in T cells from almost all types of non-Hodgkin lymphoma 
(NHL)(Xerri, Chetaille et al. 2008; Muenst, Hoeller et al. 2010; Nunes, Wong et 
al. 2012; Riches, Davies et al. 2013) and is likely a marker of exhaustion in other 
types of NHL.  
1.32 
Role of PD-1 in regulating B cell immunity using mouse model 
In contrast to the established function of PD-1 in regulation of T cell tolerance, 
the potential role of PD-1 in regulating human B cell survival and activation have 


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not been clearly studied. Data generated using a PD-1 or PD-1 ligand knock-out 
mouse model revealed that PD-1 regulates late germinal center B cell survival 
and the formation of long-lived plasma cells(Good-Jacobson, Szumilas et al. 
2010). PD-1 is also believed to regulate antibody diversification and B cell 
immunity (Kawamoto, Tran et al. 2012; Cubas, Mudd et al. 2013). Thus these 
latter studies support a direct role of PD-1 pathway in regulating B cell survival 
and immunity. 
1.33 
Expression of PD-1 in neoplastic B cells in CLL and other B-NHL 
Accumulating evidence has emerged in regards to the expression of PD-1 in 
multiple types of non-Hodgkin lymphoma (NHL). We detected PD-1 expression 
on tumor B cells from FL, marginal zone lymphoma and Waldenstrom 
Macroglobulinemia (WM) patients (preliminary data). When the PD-1 on WM 
cell line (BCWM) was ligated with PD-1 ligands, increased proliferation and 
survival of WM tumor B cells were observed and these increases of cell 
proliferation and survival were abrogated by blocking the PD-1 pathway(Grote, 
Ziesmer et al. 2013). PD-1 expression is detected on neoplastic B cells from 
small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) 
(Xerri, Chetaille et al. 2008). In CLL, PD-1 expression is increased in CLL B 
cells compared to normal B cells (preliminary data). Additionally CLL activation 
by CD40L/CPG/IL-2 stimulation can promote further expression of PD-1(Xerri, 
Chetaille et al. 2008) and PD-L1(Brusa, Serra et al. 2013). In a co-culture system 
using CLL peripheral blood mononuclear cells (PBMC) and CLL marrow 
stromal cells (MSC, expressing PD-L2 and PD-L1, see below) to mimic cellular 
interactions in the bone marrow, CLL neoplastic B cells are selectively promoted 
for survival with the sacrifice of CLL T cell apoptosis (preliminary data). These 
data suggest that the PD-1 pathway can play a major role in supporting B cell 
lymphoma survival in the tumor microenvironment.  
1.34 
Expression of PD-1 ligands in lymph node and bone marrow in B cell lymphoma 
In addition to the evidence of PD-1 expression in B cell lymphoma, expression of 
PD-1 ligands are detected in the tissue sites of B cell lymphoma. PD-L1 
expression in the CLL tumors in the lymph node tissue is much higher than its 
counterpart in reactive lymph nodes (Ramsay, Clear et al. 2012; Brusa, Serra et 
al. 2013). PD-L2 is constitutively expressed and PD-L1 expression is induced in 
CLL bone marrow derived stromal cells (preliminary data). PD-L1 expression is 
increased in tumor B cells in FL lymph nodes compared to its counterpart in 
reactive nodes (Ramsay, Clear et al. 2012). Additionally, soluble PD-L1 levels in 
the peripheral blood in diffuse large B cell lymphoma impacts the patient’s 
overall survival (Fest, Rossille et al. 2013). 
1.4 
Research Hypothesis 
Given the evidence of PD-1 and its ligands expression in neoplastic lymphoma cells and 
the tumor microenvironment, we hypothesize that the PD-1 pathway can play a major 
role in B cell lymphoma progression in lymph node and bone marrow, key tissue sites 
of tumor microenvironment. Blocking the interactions of PD-1 with its ligands will not 
only activate T cell function, but also directly block the survival/proliferating signal of 
neoplastic B cells  
 
Preliminary clinical activity of PD-1 blockade in B cell lymphoma 
To support our hypothesis, clinical benefits of blocking PD-1 in lymphoma have been 
observed. In relapsed diffuse large B cell lymphoma (DLBCL), PD-1 blockade after 


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autologous stem cell transplant achieved ~50% overall response rate in patients who had 
residual disease after transplant (Armand, Nagler et al. 2013). In relapsed follicular 
lymphoma (FL), an ~66% ORR and ~50% CR were observed with the combination 
therapy of rituximab and anti-PD-1 antibody (Westin, Chu et al. 2012). However, the 
potential activity of PD-1 blockade on CLL and other types of indolent B-NHL have not 
been studied. The relationship of expression of PD-1 and its ligands in tumor and their 
microenvironment with the clinical activity of PD-1 blockade have not been investigated. 
Thus in this proposal, we wish to test the potential activity and safety of MK-3475 in 
relapsed CLL/SLL, FL, WM and marginal zone lymphoma. 
1.5 
Treatment (MK-3475), 200 mg intravenous, every three week 
MK-3475 (previously known as 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. 
1.51 
Clinical Trial Data 
As of 18-Oct-2013, 1,000 patients have been treated with MK-3475 at several 
dose schedules, including 10 mg/kg every 2 weeks. MK-3475 has been generally 
well tolerated, as expected based on preclinical findings and other anti-PD-1 
monoclonal antibodies. As of 18-Oct-2013 no serious infusions reactions have 
been reported in the first human clinical trial (PN001). Less than 1% of patients 
thus far assayed had confirmed positive anti-drug antibody (ADA) samples and 
among these, no or no clear impact on exposure has been observed. There is no 
contraindication to further clinical investigation with MK-3475. 
Pharmacokinetics were as expected, based on MK-3475 being an IgG mAb and 
based on preclinical data, which support dosing once every 2 or 3 weeks. MK-
3475 monotherapy induces an ORR of 25%/27% in patients with ipilimumab 
exposed melanoma by central independent RECIST and oncology 
review/investigator assessed irRC, respectively. MK-3475 monotherapy induces 
an ORR of 39%/43% in patients with ipilimumab-naive melanoma by central 
independent RECIST and oncology review/investigator assessed irRC, 
respectively. These responses are remarkably durable. 
 
The preliminary 1-year survival rate for patients, many of whom have had 
multiple therapies, including ipilimumab, who receive MK-3475 is 81%. MK-
3475 monotherapy induces an ORR of 21%/24% in patients with previously-
treated NSCLC by central independent RECIST/investigator assessed irRC, 
respectively, with these responses also remarkably durable. Preliminary data 
suggest higher levels of PD-L1 expression in tumors of NSCLC are associated 
with increased activity (ORR 67% by investigator assessed irRC/57% by central 
independent RECIST); additional data are required to define the optimal PD-L1 
cut point. The most commonly reported treatment emergent AEs experienced are 
fatigue (43.8%), nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhoea 
(22.3%) and rash (21.5%). Immune-related adverse events were reported in 
21.4% of melanoma patients; most of these events (15.8%) were considered 
drug-related by the investigator. The most commonly reported immune-related 
adverse events across the dose-schedules are rash (3.2%), pruritus (2.9%), 
vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), diarrhea (2.2%), and 
pneumonitis (1.9%). Review of the overall benefit:risk ratio of MK-3475 favors 
enrollment of eligible patients into clinical trials of MK-3475. The preliminary 


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data suggest that a dose of MK-3475 at 2 mg/kg Q3W is appropriate for patients 
with melanoma. 
1.52 
Rationale for Dose Selection/Regimen/Modification 
The dose regimen of 200 mg Q3W of MK-3475 is planned for all urothelial 
cancer trials. 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 MK-3475. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 
2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels 
were well tolerated and no dose-limiting toxicities were observed.  This first in 
human study of MK-3475 showed evidence of target engagement and objective 
evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No maximum tolerated dose (MTD) has been identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects 
receiving MK-3475 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 MK-3475 at 2 mg/kg versus 10 
mg/kg Q3W.  The overall response rate (ORR) was 26% (21/81) in the 2mg/kg 
group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)).  The 
proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-
related AEs, serious drug-related AEs, death or discontinuation due to an AE was 
comparable between groups or lower in the 10 mg/kg group.   
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 MK-3475 to a clinically meaningful extent.  Taken 
together, these data support the use of lower doses (with similar exposure to 2 
mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being evaluated in 
NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated 
in head and neck cancer in PN012, which are expected to provide additional data 
supporting the dose selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based 
on simulation results indicating that 200 mg will provide exposures that are 
reasonably consistent with those obtained with 2 mg/kg dose and importantly 
will maintain individual patient exposures within the exposure range established 
in melanoma as associated with maximal clinical response. A population PK 
model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 
subjects from PN001. The distribution of exposures from the 200 mg fixed dose 
are predicted to considerably overlap those obtained with the 2 mg/kg dose, with 
some tendency for individual values to range slightly higher with the 200 mg 
fixed dose.   The slight increase in PK variability predicted for the fixed dose 


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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.  
1.6 
Ibrutinib in relapsed CLL and justification of combined therapy with anti-PD-1  
Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a critical kinase in 
regulating B cell receptor signal and B cell development. As a single therapy, Ibrutinib 
has shown significant activity in relapsed CLL patients with an overall response rate of 
70% in all groups of CLL patients {Byrd, 2013 #884}.  This study has led to FDA 
approval of Ibrutinib in relapsed CLL in 2014 and Ibrutinib has become a standard 
therapy for relapsed CLL since. In addition to its activity in blocking BTK, Ibrutinib was 
also shown to inhibit interleukin-2-inducible kinase (ITK) in T lymphocytes of CLL 
patients and reverse a Th2 immune profile into a Th1 immune response {Dubovsky, 2013 
#837}. Recent data generated in mouse models of lymphoma that are intrinsically 
insensitive to Ibrutinib showed that Ibrutinib was able to enhance the antitumor T-cell 
immune responses triggered by PD1/PD1-L blockade {Sagiv-Barfi, 2015 #887}. Thus 
Ibrutinib and anti-PD-1 antibody should be tested clinically for relapsed CLL including 
Richter’s transformation for their combined efficacy and safety. 
1.7 
Idelalisib in relapsed CLL and justification of combined therapy with anti-PD-1  
Idelalisib is an inhibitor of the delta isoform of phosphatidylinositol 3-kinase. The 
clinical efficacy of Idelalisib as a single agent or in combination with rituximab in 
relapsed CLL had been demonstrated in several trials and were shown to associate with 
70-80% overall response rate {Furman, 2014 #894} {Brown, 2014 #892}. These studies 
led to FDA approval of Idelalisib for relapsed CLL in 2014. Idelalisib has become a 
standard therapy since that time for relapsed CLL patients. PI3K delta is critical signal to 
regulate the function of T regulatory cell {Patton, 2006 #899} and PI3K delta inhibition 
has been shown to inhibit Treg function and promote CD8 T cell activity to induce tumor 
regression in mouse model {Ali, 2014 #1018}.  In melanoma, the combination therapy of 
CTLA-4 blocking antibody (ipilimumab, inhibiting Treg function) with anti-PD-1 
showed increased efficacy {Larkin, 2015 #937}. Thus it is reasonable to hypothesize that 
Idelalisib will enhance anti-tumor response of anti-PD-1 antibody by inhibition of Treg 
function and the clinical combination of these two should be tested in relapsed CLL 
including Richter’s transformation. 
1.8 
Correlative Research 
1.81 
To assess the potential association between PD-L1/PD-1/PD-L2 expression on 
tumor and T cells and/or PD-L1 soluble levels in plasma with clinical efficacy of 
PD-1 blockade. 
1.82 
To investigate the effects of MK-3475 on selected markers of immune 
modulation and immune profiles in peripheral blood and tumor samples (see 
laboratory correlates below). 
o Analysis of the B cell subsets (naïve B, IgM-memory B and switched-
memory B cells) at pre-/post- treatment and during therapy. 


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o T cell profiling analysis to assess the “activated” and “exhausted” T cell 
phenotypes both Pre-therapy, during therapy and post-therapy. 
o T cell subset (naïve, central and effector memory T cells and effector 
memory RA T cells) and T cell repertoire analysis at pre-/post- treatment and 
during therapy.  
o T cell functional studies by evaluating immune synapses of patients 
o Analyses for immune profiles and biomarkers, including plasma multiplex 
cytokines, quantification of serum immunoglobulins and serum free light 
chains and B lymphocyte activation status, T regulatory cell, monocyte and 
NK cells analysis are also included in this protocol. 
o Evaluation clinical responses based on the histology subtype of tumor and 
tumor mutation status of different patients  


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2.0 
Goals 
2.1 
Primary 
2.11 
Test the efficacy (overall response rate) of single-agent MK-3475 in relapsed CLL/SLL 
(Arm A), other low grade B-NHL (Arm B), and CLL with Richter’s transformation (Arm C).2.2
 
Secondary 
2.21 
Test the safety of single-agent MK-3475 in relapsed CLL/SLL (Arm A), other 
low grade B-NHL (Arm B), and CLL with Richter’s transformation (Arm C). 
2.22  
Test the overall survival, progression free survival, treatment free survival, 
duration of response and time to next therapy of single-agent MK-3475 in 
relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with 
Richter’s transformation  
(Arm C). 
2.23 
Test the complete response rate of single-agent MK-3475 in relapsed CLL/SLL 
(Arm A), other low grade B-NHL (Arm B), and CLL with Richter’s 
transformation (Arm C). 
2.24 
Test the safety of MK-3475 in combination with the signal inhibitor (either 
Idelalisib or Ibrutinib ) in relapsed CLL/SLL (Arm A) and CLL with Richter’s 
transformation (Arm C). 
2.25  
Test the progression-free survival, treatment-free survival, duration of response 
and time to next therapy, as well as overall survival of MK-3475 in combination 
with the signal inhibitor (either Idelalisib or Ibrutinib) in relapsed CLL/SLL 
(Arm A) and CLL with Richter’s transformation (Arm C). 
2.26  
Test the overall and complete response rates of MK-3475 in combination with 
the signal inhibitor (either Idelalisib or Ibrutinib in relapsed CLL/SLL (Arm A) 
and CLL with Richter’s transformation (Arm C). 
2.3 
Correlative Research 
2.31  
To assess the potential association between PD-L1/PD-1/PD-L2 expression on 
tumor and T cells and/or PD-L1 soluble levels in plasma with clinical efficacy of 
PD-1 blockade. 
2.32 
To investigate the effects of MK-3475 on selected markers of immune 
modulation and immune profiles in peripheral blood and tumor samples (see 
laboratory correlates below). 
o Analysis of the B cell subsets (naïve B, IgM-memory B and switched-
memory B cells) at pre-/post- treatment and during therapy. 
o T cell profiling analysis to assess the “activated” and “exhausted” T cell 
phenotypes both Pre-therapy, during therapy and post-therapy. 
o T cell subset (naïve, central and effector memory T cells and effector 
memory RA T cells) and T cell repertoire analysis at pre-/post- treatment and 
during therapy.  
o Analyses for immune profiles and biomarkers, including plasma multiplex 
cytokines, quantification of serum immunoglobulins and serum free light 
chains and B lymphocyte activation status, T regulatory cell, monocyte and 
NK cells analysis are also included in this protocol. 


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o Evaluation clinical responses based on the histology subtype of tumor and 
tumor mutation status of different patients  
2.33 
Examine T-cell immune synapse function and expression/location of  
co-stimulatory and co-inhibitory molecules (including effector molecules) as 
potential biomarkers to response for anti-PD-1 immune checkpoint blockade 
immunotherapy. Motility assays will assess the effect of anti-PD-1 therapy on  
T-cell motility (mimicking extravasation into the tumor microenvironment, 
TME).


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3.0 
Patient Eligibility 
3.1 
Inclusion Criteria   
A. Inclusion criteria for CLL/SLL patients (Arm A) only: 
3.11 
Diagnosis of CLL according to the NCI criteria (Cheson, 1996 and Hallek 2008) 
or SLL according to the WHO criteria (Harris, 1999). 
 
This includes previous documentation of: 
• 
Biopsy-proven small lymphocytic lymphoma (Harris, 1999) 
or 
• 
Diagnosis of CLL according to NCI working group criteria (Cheson, 1996 
and Hallek 2008) as evidenced by all of the following:  
 
 
Peripheral blood B cell count of  > 5 x 109/L consisting of small 
to moderate size lymphocytes 
 
 Immunophenotyping consistent with CLL defined as: 
o The predominant population of lymphocytes share both  
B-cell antigens [CD19, CD20 (typically dim expression), or CD23] 
as well as CD5 in the absence of other pan-T-cell markers (CD3, 
CD2, etc.) 
o Clonality as evidenced by κ or λ light chain expression (typically 
dim immunoglobulin expression) or other genetic method (e.g. 
IGHV analysis) 
NOTE: Splenomegaly, hepatomegaly, or lymphadenopathy are not required for the 
diagnosis of CLL 
 Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded 
by demonstrating a negative FISH analysis for t(11;14)(IgH/CCND1) on 
peripheral blood or tissue biopsy or negative immunohistochemical 
stains for cyclin D1 on involved tissue biopsy. 
 
3.12 
Patients must be previously treated with at least one prior line of therapy.  
EXCEPTION: CLL patients with Richter’s transformation or Hodgkin 
transformation do not need prior therapy to enroll. 
NOTE: 
a. Prior chemotherapy or biologic novel therapy or anti-cancer monoclonal 
antibody based therapy for treatment of CLL will be considered prior 
therapy.  Nutraceutical treatments with no established benefit in CLL 
(such as epigallocatechin gallate or EGCG, found in green tea or other 
herbal treatments) will not be considered “prior treatment”. 
b. Prior oral corticosteroid therapy for an indication other than CLL will not 
be considered “prior treatment”. 
c. Previous use of corticosteroids in the combination with other therapy for 
treatment of autoimmune complications of CLL does constitute prior 
therapy for CLL.
3.13 
Patient must meet one of the following: 
 


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• 
CLL/SLL patients must have progressive disease with any one of the 
following characteristics based on standard criteria for treatment as defined 
by the NCI-WG 1996 (Cheson, 1996 and Hallek, 2008).  
1. Symptomatic CLL characterized by any one of the following: 
 
a. Weight loss ≥ 10% within the previous 6 months 
 
b. Extreme fatigue attributed to CLL 
 
c. Fevers ≥100.5oF for 2 weeks without evidence of infection 
 
d. Drenching night sweats without evidence of infection  
2. Evidence of progressive bone marrow failure with hemoglobin ≤ 11 g/dL 
or platelet count ≤ 100 x 109/L  
3. Symptomatic or progressive lymphadenopathy, splenomegaly, or 
hepatomegaly  
 
Note: Marked hypogammaglobulinemia or the development of a monoclonal protein in 
the absence of any of the above criteria for active disease are not sufficient for protocol 
therapy. 
 
OR 
• 
Biopsy proven Richter’s transformation or Hodgkin transformation of the 
CLL.  NOTE: Both untreated and previously treated patients in this category 
can be enrolled. They do not need to meet the progressive disease criteria in 
first bullet as long as measurable disease can be detected by PET/CT or CT 
(≥1.5 cm in diameter). 
 
B. Inclusion Criteria for low grade B-NHL patients only: 
3.14  
Histologically confirmed relapsed (response to last treatment ≥ 6 months 
duration) or refractory (no response to last treatment or response duration < 6 
months) indolent/low grade B cell NHL.  NOTE: If patient has received previous 
anti-PD-1 or anti-PDL-1 consult with study chair.   
 
• 
Follicular lymphoma, grades 1, 2 and 3  
• 
Extranodal marginal zone B-cell lymphoma of MALT type  
• 
Splenic and nodal marginal zone lymphoma 
• 
Lymphoplasmacytic lymphoma including Waldenstrom Macroglobulinemia  
 
NOTE: Criteria for diagnosis can be found in the following reference: J Clin 
Oncol 17(4):1244-53, 1999.  
 
3.15  
Measurable disease (at least 1 lesion of ≥ 1.5 cm in diameter) as detected by CT 
or the CT images of the PET/CT. NOTE: Patients with Waldenstrom 
Macroglobulinemia are not required to have measurable disease by CT or 
PET/CT if monoclonal protein is detectable by serum protein electrophoresis 
and/or IgM level is at least 2 times upper limit of normal. 
C. Inclusion Criteria for CLL with Richter’s transformation (Arm C) only: 
3.16 
CLL diagnosis confirmed as 3.11 have biopsy –proven Richter’s 
transformation.  NOTE: Both untreated and previously treated patients in this category 
can be enrolled as long as measurable disease can be detected by PET/CT or CT (≥1.5 cm 
in diameter). 


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D. Inclusion Criteria for all patients: 
3.17 
Age ≥18 years. 
 
3.18 
ECOG Performance Status (PS) 0 or 1 (Appendix III). 
 
3.19 
The following laboratory values obtained ≤14days prior to registration.  
• 
Creatinine ≤ 1.5 X upper limit of normal (ULN) OR Creatinine Clearance ≥ 
60 mL/min for subject with creatinine levels > 1.5 X institutional ULN  
• 
Platelet count ≥25 x 109/L 
• 
Absolute neutrophil count ≥ 0.5X109/L  
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) unless due to Gilbert’s 
disease. If total bilirubin is >1.5 x ULN, a direct bilirubin should be 
performed and must be ≤ upper limit of normal   
• 
AST (SGOT) or ALT (SGPT) ≤ 2.5 X ULN   
 
3.19a 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.19b Provide informed written consent. 
 
3.19c 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
Note:  During the Active Monitoring Phase of a study (i.e., active treatment and 
observation), participants must be willing to return to the consenting institution 
for follow-up. 
 
3.19d Willing to provide bone marrow, tissue, and blood samples for correlative 
research purposes (see Sections 6.2, 14.0, and 17.0). 
 
3.19e 
Must have failed or be unable to tolerate or refused other available FDA 
approved effective therapies.  NOTE: Patients should not have other treatment 
options considered curative. 
3.2 
Exclusion Criteria  
3.21  
Currently participating in or has participated in a study of an investigational 
agent or using an investigational device ≤ 28 days prior to registration. 
 
3.22  
Receiving systemic steroid therapy or any other form of systemic 
immunosuppressive therapy ≤ 7 days prior to registration.  
 EXCEPTIONS: 
• 
Low doses of steroids (≤ 20 mg of prednisone or equivalent dose of other 
steroid/day).  
• 
Previous use of corticosteroids is allowed. 
• 
After initiation of MK-3475 therapy, steroid can be used for management of 
potential immune mediated AE for less than 8 weeks of therapy. 
• 
Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids 
(with minimal systemic absorption) are permitted. 
 


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3.23  
Prior anti-cancer monoclonal antibody ≤ 28 days prior to registration or who has 
not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier.  
3.24  
Prior chemotherapy or radiation therapy ≤ 14 days prior to registration or who 
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent.. 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
3.25  
Known additional malignancy that is progressing or requires active treatment.  
EXCEPTIONS (these following exceptions are permitted to enroll in this trial): 
• 
Basal cell carcinoma or squamous cell carcinoma or melanoma of the skin 
that has undergone or will undergo potentially curative therapy.    
• 
In situ cervical cancer that has undergone or will undergo potentially curative 
therapy.   
3.26  
Active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune 
disease/syndrome difficult to control in the past.   
EXCEPTIONS:  
• 
Subjects with vitiligo or resolved childhood asthma/atopy would be an 
exception to this rule. 
• 
Subjects that require intermittent use of bronchodilators or local steroid 
injections would not be excluded from the study. 
• 
Subjects with hypothyroidism stable on hormone replacement, diabetes or 
Sjorgen’s syndrome are permitted for the study.  
• 
Patients who have a positive Coombs test but no evidence of hemolysis are 
permitted for participation. 
• 
Patients with psoriasis not requiring systemic treatment are permitted for 
participation. 
• 
Conditions not expected to recur in the absence of an external trigger are 
permitted to enroll. 
 
3.27  
Evidence of interstitial lung disease or active, non-infectious pneumonitis. 
3.28  
Active infection requiring systemic therapy. NOTE: When the infection is 
controlled, patients are permitted for this study. 
3.29a  Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 


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3.29b Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic, and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment 
 
3.29c 
Known to be HIV positive.  
 
3.29d Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).  NOTE: Patients with active hepatitis B defined by 
hepatitis B surface antigen positivity or core antibody positivity in the presence 
of hepatitis B DNA are not eligible for this study. Patients with a positive 
hepatitis B core antibody but with negative hepatitis B DNA may participate, but 
must have hepatitis serologies and hepatitis B DNA monitored periodically by 
the treating physician.  
 
NOTE: IVIG can cause a false positive hepatitis B serology. If patients receiving 
routine IVIG have core antibody or surface antigen positivity without evidence of 
active viremia (negative hepatitis B DNA) they may still participate in the study, 
but should have hepatitis serologies and hepatitis B DNA monitored periodically 
by the treating physician. 
3.29e 
Received a live vaccine ≤ 30 days prior to registration. 
3.29f 
New York Heart Association Classification III or IV cardiovascular disease 
(Appendix I) or Recent myocardial infarction or unstable angina pectoris or 
unstable cardiac arrhythmia (<30 days). 
3.29g Active CNS lymphoma or cerebrospinal fluid involvement with malignant 
lymphoma cells that requires therapy. 
3.29h Has a clinically significant coagulopathy per investigator’s assessment. 
 
3.29i 
Has received an allogenic stem cell transplant.  
3.3 
Continuation Phase Exclusion Criteria 
A. 
Exclusion criteria for patients enrolling on the CLL Arms (Arm A and Arm C) for the 
combination therapy including IBRUTINIB or IDELALISIB: 
3.31 
Is chronically taking a strong CYP3A inhibitor or inducer and cannot be 
switched to an alternative agent at least 7 days prior to Idelalisib or Ibrutinib 
initiation (See Appendix VII for examples) that in the opinion of 
investigator/treating physicians precludes utilization of either Ibrutinib or 
Idelalisib. Caution is recommended for patients taking moderate inhibitors of 
CYP3A.  
 
B. 
Exclusion criteria for patients enrolling on the CLL arms (Arm A and Arm C) for the 


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combination therapy including IDELALISIB arm: 
3.32 
Is chronically taking a sensitive CYP3A substrate or a CYP3A substrate with 
a narrow therapeutic index and cannot be switched to an alternative agent at 
least 7 days prior to study initiation (See Appendix VII for examples) that in the 
opinion of investigator/treating physicians precludes utilization of Idelalisib 
3.33 
A history of chronic diarrhea, colitis, or intestinal perforation that in the opinion 
of the investigator precludes utilization of Idelalisib. 


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4.0 
Test Schedule  
4.1  
MK-3475 single-agent therapy for both CLL (Arms A and C) and B-NHL (Arm B) 
 
 
Active Monitoring Phase 
Tests & Procedures 
Days Prior to 
Registration 
(Screening phase) 
Prior to each 
cycle, 
beginning 
with cycle 21, 
13  
Response 
Evaluation1 
at 3, 6, and 
12 months 
of therapy 
Observation 
(every 90 days ± 
14 days)  
At time of 
progression19 
≤30 days 
≤14 days 
Complete medical history  
X 
 
 
 
 
 
Adverse event assessment 
 
X 
X 13 
X 
X 
X 
Physical exam, including weight, and vital 
signs, ECOG PS 
 
X 
X13 
X 
X 
X 
Height 
 
X 
 
 
 
 
Tumor measurement by physical exam 
(CLL/SLL arm only) 2 
 
X2 
X13 
X 
X 
X 
Peripheral blood immunophenotyping by 
flow cytometry  
X3 
 
 
 
 
 
CBC with differential and reticulocytes16 
 
X 
X13 
X 
X 
X 
Serum pregnancy test 
 
X4 
 
 
 
 
Peripheral smear 
 
X 
 
 
 
 
Chemistry group (SGOT [AST], SGPT 
[ALT],  total bilirubin[T-Bil],  serum 
creatinine,  alkaline phosphatase, direct 
bilirubin only when T-Bil elevated) 
 
X 
X 
X 
X 
X 
Uric acid, phosphate, calcium, potassium, 
sodium 
 
X 
 
 
 
 
HBsAg, Hep C Ab, HB core antibody 
 
X 
 
 
 
 
IGHV (CLL/SLL arm only) 
X5 
 
 
 
 
 
Bone marrow biopsy/aspirate 
X6 
 
 
X 7 
 
 
Serum protein electrophoresis (SPEP)  
 
X8 
 
X8 
 
 


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Active Monitoring Phase 
Tests & Procedures 
Days Prior to 
Registration  
(Screening phase) 
Prior to each 
cycle, 
beginning 
with Cycle 
21, 13 
Response 
Evaluation1: 
at 3, 6, and  
12 months of 
therapy 
Observation  
(every 90 days ± 
14 days) 
At time of 
progression19 
≤30 days 
≤14 days 
Beta-2-microglobulin (CLL/SLL arm only) 
 
X 
 
 
 
 
Serum quantitative immunoglobulins (IgG, 
IgA, IgM) 
 
X8 
X (IgM 
only)15 
X8 
 
X8 
Coombs test (monospecific direct coombs 
IgG and C3) 
 
X 
 
 
 
 
TSH and Free T4 
 
X 
 
X17 
 
 
CD4 T cell number and LDH 
 
X 
 
X 
 
X 
CT scan chest, abdomen, pelvis (may use 
CT portion of the PET/CT)14 
X 
 
 
X 
 
X 
Mayo confirmation of tumor diagnosis 
(NHL arm only) or CLL with 
Richter/Hodgkin transformation 
X9 
 
 
 
 
 
Mandatory tissue/node biopsy (see Section 
17.0) 
X18, R 
 
 
 
 
X18, R 
Evaluation of MRD by sensitive flow 
cytometry (CLL/SLL arm only) 
 
 
 
X10 
 
 
Mandatory blood specimens (see Section 
14.0)R 
 
X11 
For cycles 2 
and 3, and 18 
and 24 
months (if 
therapy is 
beyond 12 
months)11 
X11 
 
X11 
Mandatory research bone marrow aspirate 
specimens (see Section 14.0) 
X12,R 
 
 
X12,R 
 
 
Rochester CLL/SLL Patients Only: 
Research bone marrow core sample as per 
1827-00   
X 
 
 
X 
 
 


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1. All scheduled visits will have a window of -2 days to +7 days unless otherwise stated.  Response will be evaluated after approximately 3, 6, 
and 12 months of treatment.  If the patient remains on cycles with a length of 21 days without treatment delays, this will be at the end of cycles 
4, 9, and 17 (approximately days 189 and 357).  If the cycle length is increased due to dosing frequency changes or dose delays occur, the 
response evaluations should occur where the end of the cycles are closest to 3, 6 and 12 months (days 183 and 365), keeping in mind that this 
may occur slightly before 3, 6, or 12 months.  Response evaluation at 3, 6, and 12-month time points unless treatment has been 
stopped/completed and then the response evaluation can be performed between 2-8 weeks after last therapy. 
Note: all patients who received at least 2 cycles of treatment should be evaluated for formal clinical response either during the interval of 2-8 
weeks after the last dose of therapy or at 3, 6, and 12-month time points since therapy start, whichever occurs first. 
If patient is continuing to benefit from treatment after 12 months determined by investigator, they may continue to receive treatment up to a 
total duration of 24 months including both single-agent and combination therapy at investigator/sponsor discretion. 
2. Physical exam should measure the spleen and liver noting the maximal distance below the respective costal margins and should record the 
bidimensional diameter of the largest palpable node in each area of involvement including the following sites:  left neck (sub-mandibular, 
cervical, supra-clavicular), right neck (sub-mandibular, cervical, supra-clavicular), left axillary, right axillary, left groin (inguinal, femoral) 
and right groin (inguinal, femoral). 
3. Only applicable for CLL/SLL, marginal zone and Lymphoplasmacytic lymphoma patients, not for follicular lymphoma patients. For patients 
who have previously had full flow immunophenotyping consistent with CLL or low grade NHL performed at Mayo Clinic or other academic 
centers, repeat flow immunophenotyping is not necessary.   
4. For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
5. If patient has previously had done clinically at Mayo Clinic or other academic centers, this does not need to be repeated. 
6. Bone marrow biopsy/aspirate is required.  Baseline bone marrow biopsy/aspirate is not required if the patient has had a bone marrow 
biopsy/aspirate obtained for clinical purposes ≤90 days prior to registration however, this should be discussed with the study chair.  
7. For CLL patients only who had bone marrow involvement at baseline, a bone marrow biopsy is required at 6-months and 12 months for all 
patients with evidence of response (CR, CRi, nPR, and PR) but is not required for those with disease progression/stable disease.  For NHL 
patients, only required at 6-month and at 12-month visits for patients who have achieved clinical response and had bone marrow involvement 
at baseline. 
8. For CLL/SLL, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia and marginal zone lymphoma patients only. For SPEP, only 
required at 6-month and 12-month time points 
9.   Central review of pathology is required for confirmation of diagnosis for NHL patients or CLL patients with Richter/Hodgkin transformation 
unless patient has had a documented tissue pathology for low grade B cell NHL or Richter/Hodgkin transformation confirmed by Mayo 
pathologist or other academic centers in the history (anytime in the history).  
10. MRD testing on 6-month and on 12-month visit only for CLL patients who have a very good response (CR/CRi/CCR/nPR) only. If marrow 
samples are available, marrow MRD testing is preferred. 
11. Blood specimens will be collected and submitted at the following time points: registration, prior to cycle 2, prior to cycle 3, at 3-month,  
6-month, and 12-month time points from start of therapy, as well as at disease progression.  If patient continues therapy (single or 
combination) beyond 12 months, blood specimens will be collected at 18-month and 24-month time points from start of therapy, as well as 
disease progression. 


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12. Research bone marrow aspirate specimens must be collected at the same time when clinical bone marrow tests are required (e.g. baseline,  
6 and 12 months of therapy or other time when performed) and submitted.  If bone marrow was performed prior to consenting the patient for 
this study, a repeat bone marrow is not required to obtain the research aspirate sample at baseline.   
13.  Adverse events, CBC, Cr and LFTs must be evaluated every cycle.  For patients who tolerated therapy and have clinical benefits, they will be 
followed at each cycle for the first 6 months. Clinical response will be evaluated at 3 and 6 months. After 6 months of therapy, responsive or 
stable patients can be followed every other cycle by treating physician/provider until one or two years of total duration of therapy. However, 
patient will be followed by nurse at each cycle of treatment for adverse event assessment. They will be seen as needed by provider.  Physical 
exam and tumor measurements are required only on cycles where the patient is evaluated by the treating physician. All patients who received 
at least 6 months of therapy and have shown clinical benefit will be evaluated again at 12 months for clinical response. For patients who 
continue therapy beyond 12 months, the above schedule is recommended. Further formal response evaluation is only required if there is 
clinical sign of disease progression. Other response evaluation is per discretion of treating physician. 
14.  For Follicular lymphoma grade 3 and CLL patients with Richter’s transformation or Hodgkin transformation, PET/CT scan will be performed 
to replace CT at baseline, at 3, 6, and 12 months for response evaluation.  Scans after baseline are not required for patients with 
lymphoplasmacytic lymphoma (Waldenstrom Macroglobulinemia) if utilizing IgM as the criteria for response. If patient had measurable nodes 
at baseline, then scans should be repeated. 
15. For patients with lymphoplasmacytic lymphoma (Waldenstrom Macroglobulinemia) only when this is being used as the criteria for 
measurable disease. 
16. Reticulocytes are required at baseline for all patients. After baseline may be ordered at physician discretion. 
17. At 6 month visit.  If there is no change from baseline, further testing is not required. 
18. Research tissue/node biopsy- tissue block or slide submission is required for correlative research described in section 17.0. Repeat tissue/node 
biopsy solely for the purpose of correlative study is not required pre-registration. If a tissue biopsy is done to make a clinical diagnosis per the 
treating physician, then the tissue block (preferred) or slides should be submitted for correlative research. 
19. For Arm A and Arm C patients who go on to combination treatment, this is considered the baseline visit and lab tests before continuing to 
follow test schedule in Section 4.2. 
R Research funded (see Section 19.0). Will be charged to study and not to patient’s account. 
 


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4.2 
Continuation Phase: Combination therapy of MK-3475 with a signal inhibitor (Idelalisib or Ibrutinib) for CLL (Arm A) and CLL 
with Richter’s transformation only (Arm C) 
 
 
 
Active Monitoring Phase 
Tests & Procedures 
Prior to each cycle, 
beginning with 2nd 
cycle  of combination 
therapy1, 8  
Response Evaluation1: at 3, 
6, and 12 month of 
combination therapy 
Observation 
(every 90 days ± 14 
days)  
At time of 
progression 
Adverse event assessment 
X 8 
X 
X 
X 
Physical exam, including weight, and vital 
signs, ECOG PS 
X8 
X 
X 
X 
Tumor measurement by physical exam 
(CLL/SLL arm only) 2 
X8 
X 
X 
X 
CBC with differential and reticulocytes10 
X8 
X 
X 
X 
Chemistry group (SGOT [AST], SGPT 
[ALT],  total bilirubin[T-Bil],  serum 
creatinine,  alkaline phosphatase, direct 
bilirubin only when T-Bil elevated) 
X 
X 
X 
X 
Bone marrow biopsy/aspirate 
 
X 3 
 
 
Serum protein electrophoresis (SPEP) 
 
X4 
 
 
Serum quantitative immunoglobulins (IgG, 
IgA, IgM) 
 
X4 
 
X 
CD4 T cell number and LDH 
 
X 
 
X 
CT scan chest, abdomen, pelvis (may use 
CT portion of the PET/CT)9 
 
X 
 
X 
Mandatory tissue/node biopsy (see section 
17.0) 
 
 
 
X11, R 
Evaluation of MRD by sensitive flow 
cytometry (CLL/SLL arm only) 
 
X5 
 
 
Mandatory blood specimens (see Section 
14.0)R 
 For cycles 2 and 3 of 
combination therapy 
and 18 and 24 months 
of combination 
therapy6 
X6 
 
X6 


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Mandatory research bone marrow aspirate 
specimens (see Section 14.0) 
 
X7,R 
 
 
Rochester CLL/SLL Patients Only: 
Research bone marrow core sample as per 
1827-00   
 
X 
 
 
1. All scheduled visits will have a window of - 2 days to +7 days unless otherwise stated.  Response will be evaluated after approximately 3, 6, 
and 12 months of combination treatment. Disease measurements and lab parameters obtained after the last cycle of single-agent therapy are 
set as the baseline measurements for this phase. If the cycle length is increased due to dosing frequency changes or dose delays occur, the 
response evaluations should occur where the end of the cycles are closest to 3, 6, and 12 months of combination treatment, keeping in mind 
that this may occur slightly before 3, 6 or 12 months.  Response evaluation at 3, 6, and 12-month time point unless treatment has been 
stopped/completed and then the response evaluation can be performed between 2-8 weeks after last dose of pembrolizumab therapy. 
Note: all patients who received at least 2 cycles of treatment should be evaluated for formal clinical responses either during the interval of 2-8 
weeks after the last dose of pembrolizumab therapy or at 3, 6, and 12-month time point since therapy start, whichever occurs first. 
If patient is continuing to benefit from treatment after 12 months determined by investigator, they may continue to receive treatment up to a 
total duration of 24 months including both single-agent and combination therapy at investigator/sponsor discretion. 
2. Physical exam should measure the spleen and liver noting the maximal distance below the respective costal margins and should record the 
bidimensional diameter of the largest palpable node in each area of involvement including the following sites:  left neck (sub-mandibular, 
cervical, supra-clavicular), right neck (sub-mandibular, cervical, supra-clavicular), left axillary, right axillary, left groin (inguinal, femoral) 
and right groin (inguinal, femoral). 
3. For CLL patients only who had bone marrow involvement at baseline, a bone marrow biopsy is required at 6-months and 12-months for all 
patients with evidence of response (CR, CRi, nPR, and PR) but is not required for those with disease progression/stable disease. 
4. For CLL/SLL, lymphoplasmacytic lymphoma patients only. For SPEP, repeat only is required at 6 and 12 months. 
5.   MRD testing on 6-month and on 12-month visit only for CLL patients who have a very good response (CR/CRi/CCR/nPR) only. If marrow 
samples are available, marrow MRD testing is preferred. 
6. Blood specimens will be collected and submitted at the following time points: prior to cycle 2, prior to cycle 3, at 3, 6, and  
12- month time point for combination therapy, as well as at the disease progression. If patient continues therapy (single or combination) 
beyond 12 months, blood specimens will be collected at 18-month and 24-month time points from start of therapy, as well as disease 
progression. 
7. Research bone marrow aspirate must be collected at the same time when clinical bone marrow tests are required (e.g. 6 and 12 months of 
therapy or other time when performed) and submitted.    
8.   Adverse events, CBC, Cr and LFTs must be evaluated every cycle.  For patients who tolerated therapy and have clinical benefits, they will be 
followed at each cycle for the first 6 months. Clinical response will be evaluated at 6 months. After 6 months of therapy, responsive or stable 
patients can be followed every other cycle by treating physician/provider until one year of total duration of therapy. However, patient will be 
followed by nurse at each cycle of treatment for adverse event assessment. They will be seen as needed by provider.  Physical exam and 
tumor measurements are required only on cycles where the patient is evaluated by the treating physician. All patients who received at least 6 
months of combination therapy and shown clinical benefit will be evaluated again at 12 months for clinical response. For patients continuing 


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therapy beyond 12 months, the above schedule is recommended. Further formal response evaluation is only required if there is clinical sign of 
disease progression. Other response evaluation is per discretion of treating physician. 
9.  For CLL patients with Richter’s transformation or Hodgkin transformation, PET/CT scan will be performed to replace CT at all time points 
(month 3, 6, and 12 of the combination therapy) and disease progression for response evaluation.   
10. Reticulocytes are required at baseline for all patients.  After baseline, may be ordered at physician discretion. 
11. Research tissue/node biopsy tissue block or slide submission is required for correlative research described in section 17.0. If a tissue biopsy is 
done to make a clinical diagnosis per the treating physician, then the tissue block (preferred) or slides should be submitted for correlative 
research. 
R Research funded (see Section 19.0).  Will be charged to study and not to patient’s account. 
 


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5.0 
Grouping Factor:  
 
5.1 
Treatment Arm: Arm A (CLL/SLL and CLL with Richter’s transformation) vs Arm B 
(low grade NHL)  vs. Arm C (CLL with Richter’s transformation)   
 
Note:  CLL patients with Richter’s transformation or Hodgkin’s transformation will be 
included in Arm A and C.   
 
As per MCCC Addendum 2: An arm (Arm C) with CLL patients with Richter’s 
transformation only is added to the study. 
 
6.0  
Registration Procedures 
6.1 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at
 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page 
and detail the process for 
completing and confirming patient registration.  Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent.  Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
.  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.2 
Correlative Research 
A mandatory correlative research component is part of this study. The patient will be 
automatically registered onto this component (see Sections 3.19c, 14.0, and 17.0). 
6.3 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
).  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Prior to accepting the registration, registration application will verify the following: 
• 
IRB approval at the registering institution 


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• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of CLL/NHL at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.5 
Treatment cannot begin prior to registration and must begin ≤ 14 days after registration. 
6.6 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.7 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.8 
Treatment on this protocol must commence at Mayo Clinic Rochester, Mayo Clinic in 
Florida, or Mayo Clinic in Arizona under the supervision of a Hematologist. 
6.9a 
Study drug is available on site.  
6.9b 
Continuation Phase  (Combination Treatment with  MK-3475 and 
Ibrutinib/Idelalisib):  To register a patient fax 
) a completed continuation 
phase eligibility checklist to the Registration Office between 8 a.m. and 4:30 p.m. central 
time Monday through Friday. 


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7.0 
Protocol Treatment  
7.1 
Treatment Schedule for all three arms  
Agent 
Dose Level 
Route 
Day 
Cycle Length 
MK-3475 
200 mg 
IV 
Day 1 
21 days 
CLL/SLL 
patients only: 
Bactrim DS* 
1 tablet once 
daily 
Oral 
Three times per 
week while on 
treatment 
*If a patient has sulfa allergy or could not tolerate Bactrim, alternative PCP prophylaxis 
is allowed at the discretion of treating provider. For patients continuing on combination 
therapy, PCP prophylaxis is optional. Bactrim can be changed to alternative PCP 
prophylaxis. 
 
Note: Tumor lysis syndrome has not been observed with MK-3475 therapy. Standard 
prophylaxis for tumor lysis syndrome can be considered prior to therapy. 
 
Note: Each cycle of treatment is 21 days. If patient experienced adverse events which 
required dosing delay (see Section 8.0), the new dosing interval (increased interval) can 
be defined as a new cycle length. If CLL or NHL patients have achieved CMR/CR/CRi 
(MRD negative CR for CLL patients) confirmed by bone marrow or CT/PET evaluation, 
patients could continue the treatment for 2 more cycles and stop the treatment at the 
discretion of the treating provider. If patient experiences disease relapse after stopping 
therapy due to CMR/CR, the previous treatments can be restarted.  The designed 
maximum length of treatment is 12 months (365 days). 
 
Note: If patient is continuing to benefit from treatment after 12 months, they may 
continue to receive treatment up to 24 months at investigator/sponsor discretion 
 
7.2 
Timing of Dose Administration for all three arms 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the test schedule (Section 
4.0).  Trial treatment may be administered up to 2 days before or 7 days after the 
scheduled Day 1 of each cycle due to administrative reasons. 
 
Note:  For patients who tolerated therapy and have clinical benefits, they will be 
followed at each cycle for the first 6 months. Clinical response will be evaluated at 3 and 
6 months. After 6-months of therapy, responsive or stable patients can be followed every 
other cycle by treating physician/provider until one year of total duration of therapy. 
However, patient will be followed by nurse at each cycle of treatment for adverse event 
assessment. They will be seen as needed by provider. All patients who received at least 6 
months of therapy and shown clinical benefit will be evaluated again at 12 months for 
clinical response. For patients continuing therapy beyond 12 months, the above schedule 
is recommended. Further formal response evaluation is only required if there is clinical 
sign of disease progression. Other response evaluation is per discretion of treating 
physician. 
7.3 
For CLL patients with or without Richter’s transformation (Arm A and Arm C), if a 
patient developed progressive disease (not tumor flare) at any time of the single-agent 
(MK-3475) therapy, or has stable disease without partial remission at the response 


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evaluation at month 3 of the single-agent (MK-3475) therapy, a commercially available 
FDA-approved CLL signal inhibitor can be added to MK-3475 (remain at the dose 
200mg IV every 3 weeks). In this clinical scenario, if the patient had not used Ibrutinib in 
the past, Ibrutinib is recommend to be added using the standard FDA approved dose. 
However, the dose of Ibrutinib can be modified by treating physician based on 
concomitant medications or other clinical status. If the patient had progressed or had 
intolerable adverse events on Ibrutinib, Idelalisib is recommended to be added using the 
standard FDA approved dose. The dose of Ibrutinib or Idelalisib can be reduced/adjusted 
due to adverse events or concomitant medications according to the package inserts of the 
individual agent. If the patient had used both Ibrutinib and Idelalisib in the past, it is at 
the discretion of investigator/treating physician to decide which FDA-approved oral CLL 
therapy to use according to the package inserts of the individual agent and clinical status 
of the patient. 
Treatment Schedule for Combination Therapy with MK-3475 and Ibrutinib 
Agent 
Dose Level 
Route 
Day 
Cycle Length 
MK-3475 
200 mg 
IV 
Day 1 
21 days** 
Ibrutinib 
420 mg 
Oral 
Once daily 
**If the dosing interval was increased due to adverse events while receiving  
single-agent MK-3475, continue with the increased dosing interval the patient was 
receiving for the last cycle of single-agent MK-3475 
 
Treatment Schedule for Combination Therapy with MK-3475 and Idelalisib 
Agent 
Dose Level 
Route 
Day 
Cycle Length 
MK-3475 
200 mg 
IV 
Day 1 
21 days** 
Idelalisib 
150 mg  
Oral 
Twice daily 
 
**If the dosing interval was increased due to adverse events while receiving single-agent 
MK-3475, continue with the increased dosing interval the patient was receiving for the 
last cycle of single-agent MK-3475. 
7.4 
For patient who received ibrutinib previously: 
Note: due to the observed ibrutinib withdrawal syndrome in selected CLL patients who 
had received ibrutinib before, steroid use in the format of 0.5 mg to 2 mg per kilogram 
body weight prednisone or equivalent is allowed with a gradual taper to overcome the 
ibrutinib withdrawal syndrome. The duration of high dose steroid use should be within 
the first 1-3 months when patients were off ibrutinib  
7.5 
If CLL or NHL patients have achieved CMR/CR (MRD negative CR for CLL patients) 
confirmed by bone marrow or CT/PET evaluation, patients could continue the treatment 
for 2 more cycles and stop the treatment at the discretion of the treating provider.  If 
patient experiences disease relapse after stopping therapy due to CMR/CR, the previous 
treatments can be restarted.  The designed maximum length of active treatment with MK-
3475 is 12 or 24 months. 
7.6 
Total duration of treatment including both single-agent and combination therapy is a 
maximum of 12 months.  If the patient remains on cycles with a length of 21 days 
without treatment delays, this will be 17 cycles total.  If the cycle length is increased due 
to dosing frequency changes or dose delays occur, the number of cycles will be reduced 
to not exceed 12 months (365 days) of treatment total. NOTE: If patient is continuing to 
benefit from treatment after 12 months, they may continue to receive treatment up to a 
total duration of 24 months including both single-agent and combination therapy at 


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investigator/sponsor discretion. 
7.7 
At the end of the trial therapy with MK-3475, signal inhibitor can be continued or 
stopped at the discretion of the treating physicians.  


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8.0 
Dose modification based on Adverse Events 
8.1  
MK-3475 Dose Levels  
 
Dose 
Level 
MK-3475** 
 0* 
200 mg IV Day 1 every 21 days 
*Dose level 0 refers to the starting dose. 
**If dose modifications are needed, the dosing interval may be increased by 7 days each 
time, the maximal dosing interval allowed is 8 weeks. 
Note: This study will not allow dose reduction of MK-3475, only dose interval changes 
8.2 
Arms A and C Dose Modifications – NOTE: Dose hold/modification of Ibrutinib or 
Idelalisib will be based on the package insert of the individual medicine. If the patient is 
on a moderate cytochrome P450 inhibitor or inducer (see Appendix VII), caution is 
recommended and close monitoring of toxicity or efficacy of therapy is warranted. 
Providers should consult the package insert for recommendations on dose adjustment in 
the setting of drug interactions. In case an adverse event cannot be easily attributed to 
either MK-3475 or the signal inhibitor, strongly recommend to discuss with study chair 
and/or sponsor for subsequent decision. 
8.3 
MK-3475 Dose Modifications only-see table below. In case an adverse event cannot be 
easily attributed to either MK-3475 or the signal inhibitor, strongly recommend to discuss 
with study chair and/or sponsor for subsequent decision. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE 
EVENT (at least 
possibly related) 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
Gastrointestinal 
disorders1 
Enterocolitis 
Grade 2 
MK-3475 
Hold study treatment and consider infection 
evaluation with C. diff toxin. If rule out c.diff, 
anti-diarrheal treatment should be started. The 
recommended dose of loperamide is 4 mg at 
first onset, followed by 2 mg every 2-4 hours 
with oral hydration until diarrhea free 
(maximum 16 mg/day).  If symptoms are 
persistent for more than one week or 
complicated with rectal bleeding, GI 
consultation and endoscopy is recommended. 
Systemic corticosteroids or budesonide 9 mg 
daily should be initiated (e.g., 0.5 mg/kg/day of 
prednisone or equivalent).  When symptoms 
improve to Grade 1 or less, corticosteroid taper 
should be started.  If AE improves to grade 1 
or less within 4 weeks, study treatment should 
be restarted at the same dose with the same 
cycle length for the first occurrence. The cycle 


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interval will increase by one week for each 
occurrence of the same adverse events. If the 
treatment is delayed ≥ 8 weeks from last 
therapy, study treatment should be 
discontinued and go to observation if at least 2 
cycles of therapy were given, otherwise, go to 
event monitoring. 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE 
EVENT (at least 
possibly related) 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
Gastrointestinal 
disorders 
Enterocolitis 
≥ Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MK-3475 
Discontinue study treatment, GI consultation 
and endoscopy is recommended. Go to 
observation if ≥ 2 cycles were given, otherwise 
go to event monitoring. 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. 
Respiratory, thoracic 
and mediastinal 
disorders1 
Pneumonitis 
Subjects with symptomatic pneumonitis should 
immediately stop receiving study treatment and 
have an evaluation.  The evaluation may 
include bronchoscopy and pulmonary function 
tests to rule out other causes such as infection.  
If the subject is determined to have study drug 
associated pneumonitis, treat as follows: 
 
Grade 2 
Hold study treatment and treat with systemic 
corticosteroids and taper when the symptoms 
improve to grade 1 or less.  For first 
occurrence, restart at the same dose with the 
same cycle length if AE improves to Grade 1 
or less within 4  weeks when systemic steroid 
reduced to ~ prednisone 10 mg oral daily dose 
or less. If the symptoms improve to grade 1 or 
less between 4 to 8 weeks, discontinue therapy 
or consult with study chair. For second 
occurrence, discontinue study treatment and go 
to observation if ≥ 2 cycles of therapy were 
given, otherwise go to event monitoring. 
 
≥ Grade 3 
Discontinue study treatment and go to 
observation if ≥ 2 cycles of therapy were 
given, otherwise go to event monitoring. 
Recommend pulmonary evaluation including 
bronchoscopy and pulmonary function tests to 
rule out other causes.  Treat with systemic 


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corticosteroids.  The use of infliximab may be 
indicated as appropriate. May consult study 
chair. 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT (at 
least possibly related) 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
General disorders 
and administration 
site conditions 
Infusion related reaction 
≥ Grade 3 
(see Section 9.9a for 
treatment guidelines) 
 
Discontinue study treatment and go to 
observation if ≥ 2 cycles of therapy were 
given, otherwise go to event monitoring.   
Immune system 
disorders 
Immune system disorders 
– Other, specify 
 Events of Clinical 
Interest & Immune-
related Adverse Events 
(irAEs) 
(see Section 9.9b 
supportive care 
guidelines) 
 
MK-
3475 
 
Grade 2 
May hold study treatment. Steroid 
treatment may be indicated.  
Clinical AE resolves to grade 1 or less 
within 4 weeks:  Same dose and schedule. 
Clinical AE does not resolve to grade 1 or 
less within 4 weeks: hold therapy until 
AE improves to grade 1 or less and may 
prolong the dosing interval to maximal 8 
weeks.  May increase the dosing interval 
by 1 week.  May increase the dosing 
interval by 1 week for each occurrence. 
If AE does not resolve within 8 weeks of 
last therapy discontinue study treatment 
and go to observation if ≥ 2 cycles of 
therapy were given, otherwise go to event 
monitoring. 
≥ Grade 32 
Hold study treatment and discontinue if 
unable to reduce corticosteroid dose to  
< 10 mg per day prednisone equivalent 
within 8 weeks of adverse event. Consult 
with study chair as needed.  If treatment is 
discontinued, go to observation if ≥ 2 
cycles of therapy were given, otherwise 
go to event monitoring. 
 


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
(at least possibly 
related) 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
Investigations 
Neutrophil count 
decreased 
Grade 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MK-3475 
Hold study treatment and restart when resolved 
to Grade 0-1 or baseline.  May increase dosing 
interval by 1 week.  If adverse event does not 
resolve to grade 0-1 or baseline within 8 weeks 
from last therapy, discontinue study treatment 
and go to observation if ≥ 2 cycles of therapy 
were given, otherwise go to event monitoring. 
Endocrine 
disorders 
Adrenal Insufficiency 
Hyperthyroidism 
Hypothyroidism 
 
Endocrine disorders - 
Other,  
Hypopituitarism, 
Thyroiditis, 
Hypophysitis 
 
 
 
Grade 2 
Monitor hormonal levels in the appropriate 
frequency by the discretion of treating physician 
until returned to baseline values. Hormonal 
replacement or other necessary therapy is 
recommended. Consider endocrine consultation 
as needed. Hold treatment until AE improves to 
grade 1or baseline. If AE improves to grade 1 or 
baseline within 4 weeks, study treatment should 
be restarted at the same dose with the same 
cycle length for the first occurrence. The cycle 
interval will increase by one week for each 
occurrence of the same adverse events. If the 
treatment is delayed ≥8 weeks, study treatment 
should be discontinued and go to observation if 
≥2 cycles of therapy were given, otherwise go 
to event monitoring. 
 
≥ Grade 3 
Hold study treatment, consider endocrine 
consultation and discussion. Rule out infection 
and sepsis with appropriate cultures and 
imaging.  Consider treatment with 
corticosteroids 1 to 2 mg/kg daily. When 
symptoms improved to grade 1 or less, steroid 
taper may be started. Replacement of 
appropriate hormones may be required. Discuss 
with study chair for the option of continuation 
of treatment when the AE improves to grade 1 
or baseline within 8 weeks from last therapy. If 
treatment is discontinued, go to observation if  
≥ 2 cycles were given, otherwise go to event 
monitoring.  


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT (at 
least possibly related) 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
Eye disorders 
Uveitis 
Grade 1- 2 
MK-3475 
Hold treatment. Evaluation by an 
ophthalmologist is strongly 
recommended. Infectious causes will need 
to be ruled out. Treat with topical steroids 
is recommended.  For the first occurrence, 
if AE resolves within 4 weeks, study 
treatment should be restarted at the same 
dose with the same cycle length. If AE 
resolves between 4-8 weeks from the last 
therapy, the cycle interval will increase by 
one week. Discontinue treatment if 
symptoms persist despite topical 
therapies. Discontinue treatment for the 
second occurrence. If the treatment is 
delayed ≥8 weeks, study treatment should 
be discontinued and go to observation if 
≥2 cycles of therapy were given, 
otherwise go to event monitoring. 
 
≥ Grade 3 
Discontinue treatment. Evaluation by an 
ophthalmologist is strongly 
recommended. Infectious causes will need 
to be ruled out. Treat with topical or 
systemic steroids is recommended. When 
symptoms improve to grade 1 or less, 
systemic steroid taper should be started. 
Cardiac disorders 
Myocarditis Grade 1  
MK-3475 
Hold all treatment. Consult study chair. 
Resume when resolved and 
corticosteroids have been tapered, if 
applicable. If not resolved within 12 
weeks of last dose or if corticosteroids 
cannot be reduced to ≤ 10 mg prednisone 
or equivalent per day within 12 weeks, 
discontinue treatment and go to 
observation if ≥ 2 cycles of therapy were 
given, otherwise go to event monitoring. 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes. . 
 
≥Grade 2 
 
Discontinue all treatment and go to 
observation if ≥ 2 cycles of therapy were 
given, otherwise go to event monitoring. 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes. May 
administer corticosteroids. 


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Metabolism and 
nutrition disorders 
Glucose intolerance 
(Type 1 diabetes 
mellitus [if new onset] 
or Hyperglycemia Any 
Grade 
MK-3475 
Hold treatment of MK-3475. Consult with 
endocrinology to decide if T1DM is 
confirmed. If T1DM confirmed, initiate 
insulin replacement therapy. Administer 
anti-hyperglycemic in participants with 
hyperglycemia. Monitor for 
hyperglycemia or other signs and 
symptoms of diabetes. Prior to restarting, 
consult with PI or treating physician to 
assess whether further treatment is 
indicated. 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT (at 
least possibly related) 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
Other non-
hematologic 
Grade 2 
Exception: Grade 2 
alopecia and fatigue do 
not require any action. 
MK-3475 
Consider holding study treatment for 
persistent significant clinical symptoms 
until AE resolves to Grade 0-1 or 
baseline. 
Clinical AE resolves to grade 0-1 or 
baseline within 4 weeks:  Same dose and 
schedule  
Clinical AE does not resolve to grade 0- 1 
or baseline within 4 weeks:  May increase 
the dosing interval to maximal 8 weeks.  
May increase the dosing interval by 1 
week for each occurrence. 
If AE does not resolve to grade 0-1 or 
baseline within 8 weeks, discontinue 
study treatment and go to observation if ≥ 
2 cycles of therapy were given, otherwise 
go to event monitoring. 
 
≥ Grade 3 
Hold study treatment until AE resolves to 
Grade 0-1 or baseline. May increase the 
dosing interval by 1 week for each 
occurrence. 
 Consult with study chair as needed.  If 
AE does not resolve to grade 0-1 or 
baseline within 8 weeks from last therapy, 
discontinue study treatment and go to 
observation if ≥ 2 cycles of therapy were 
given, otherwise go to event monitoring.  
For any severe or life-threatening AE, 
consider discontinuing study treatment. 
 
*   Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm  
** Use the following to describe actions in the Action column: 


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 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does make up 
the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped.  
 
NOTES: 
• 
In case toxicity does not resolve to Grade 0-1 or baseline within 8 weeks after last infusion, trial 
treatment should be discontinued after consultation with the study chair.  With study chair and 
Sponsor agreement, subjects with a laboratory or non-significant adverse event still at Grade 2 or 
baseline after 8 weeks may continue treatment in the trial only if asymptomatic and controlled 
with appropriate supportive care.     
• 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of MK-3475 should be discontinued from trial treatment. 
1. Consideration should be given to MK-3475 or Idelalisib as the causative agent in the setting of 
enterocolitis/pneumonitis, if both agents are being utilized. Consultation with the study chair is 
warranted. 
2. In case of autoimmune hepatitis, when grade 3 (AST or ALT >5.0 times ULN and/or total bilirubin 
>3.0 times ULN), discontinue MK 3475 or combination therapy. Consider appropriate consultation 
and liver biopsy to establish etiology of hepatic injury. If necessary, treat with high-dose intravenous 
or oral glucocorticosteroids (prednisone equivalent 1-2 mg/kg) for 24 to 48 hours. When symptoms 
improve to grade 1 or less, a steroid taper should be started and continued. If serum transaminase 
levels do not decrease 48 hours after initiation of systemic steroids, oral mycophenolate mofetil  
500 mg every 12 hours may be given. 
 
MK-3475 will be withheld for drug-related Grade 4 hematologic toxicities per table in  
8.4, non-hematological toxicity ≥ Grade 3 including uncontrolled laboratory abnormalities, 
and severe or life-threatening AEs as per Tables in 8.3 and 8.4


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8.4 
MK-3475 Dose Modification for Hematological Toxicities (Platelet and Hemoglobin 
only) for MK-3475. 
Note: hematological toxicity is not based on CTCAE 4.0 except neutrophil, but based on 
CLL specific hematological toxicity (this table and Appendix IV). 
Dose modification guidelines for drug-related hematological (hemoglobin and platelets) 
adverse events1, 2, 3  
Toxicity 
Grade 1, 2, 3 
 
 
Decrease from 
pretreatment4 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with PI) 
CLL/NHL 
specific 
Hematologica
l Toxicity 
(appendix IV) 
 
1 
 
 
 
2 
11-24% 
decrease in 
HGB or PLT 
 
25-49% 
decrease in 
HGB or PLT 
No 
N/A 
N/A 
N/A 
3 
 
50-74% 
decrease in 
HGB or PLT 
Yes 
Toxicity 
resolves to 
Grade 0-2 
or baseline 
May increase 
the dosing 
interval by 1 
week  
Toxicity does 
not resolve 
within 8 
weeks of last 
infusion 
Permanent 
discontinuatio
n should be 
considered 
for any severe 
or life-
threatening 
event. 
Go to 
observation if 
 ≥ 2 cycles of 
therapy were 
given, 
otherwise go 
to event 
monitoring 
4 
≥75% 
decrease in 
HGB or PLT  
Yes 
Toxicity 
resolves to 
Grade 0-2 
or baseline 
May increase 
the dosing 
interval by 1 
week  
1If, at any level of decrease the platelet count is < 20,000/µL, this will be considered grade 4, unless the 
initial platelet count was ≤ 20,000 µL in which case the patient is inevaluable for toxicity referable to 
platelet counts. 
2If, at any level of decrease from the baseline value the platelet and/or hemoglobin counts are within 
normal limits or platelet count is still ≥ 100,000/µL, this will be considered a grade 0. 
3If patient has persistent cytopenia, it is recommended to repeat bone marrow evaluation to test if there 
is disease progression. 
4For patients initiated on combination therapy of a signal inhibitor with MK-3475, the pretreatment 
value is the value before addition of the signal inhibitor. 


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9.0 
Ancillary Treatment/Supportive Care  
9.1 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (42) Update of 
Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-
Based, Clinical Practice Guidelines.  J Clin Oncol 24 (19): 3187 -3205, 2006. 
9.2 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate.  Any blood transfusions 
administered must be irradiated blood products to reduce risk of transfusion 
mediated graft versus host disease in CLL and NHL patients receiving T-cell 
suppressive therapy.  Leukocyte reduction of all blood products for patients on 
protocol is also required. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.3 
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 
medication/vaccination may be required.  The provider should discuss any questions 
regarding this with the investigator.  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, the provider, and the subject. 
9.4 
Acceptable Concomitant Medications: All treatments that the provider/investigator 
considers necessary for a subject’s welfare may be administered at the discretion of the 
provider/investigator in keeping with the community standards of medical care. 
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.  If changes 
occur during the trial period, documentation of the changed medication should be 
recorded. 
 
Note: IVIG replacement therapy for CLL patients is permitted, but recommend to discuss 
with study chair for continuation. 
 
9.5 
Prohibited Concomitant Medications: Subjects are prohibited from receiving the 
following therapies during the Screening and Treatment Phase of this trial: 
• 
Anti-cancer systemic chemotherapy   
• 
Immunotherapy not specified in this protocol. Note: IVIG replacement is permitted. 
• 
Radiation therapy.  Note:  Radiation therapy to a symptomatic solitary lesion or to the 
brain may be allowed after consultation with Investigator.   
• 
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 and pneumonia vaccines for injection are 


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generally killed virus vaccines and are allowed; however intranasal influenza 
vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.  
• 
Ongoing chronic steroid therapy with a dose more than equivalent prednisone dose 
≥30mg daily for longer than 2 months. 
 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
9.6 
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. 
9.7 
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.  Steroid therapy should be strongly 
considered per table 8.3 
• 
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. 
• 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever 
or severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or 
vomiting should be hospitalized for intravenous hydration and correction of 
electrolyte imbalances. 
9.8 
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. 
For CLL patients, it is highly recommended to start PCP and viral prophylaxis 
while patients are on treatment. 
 


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9.9a 
Management of Infusion Related Reactions:  Acute infusion reactions (which can include cytokine release syndrome, angioedema, 
or anaphylaxis) are different from allergic/hypersensitive reactions, although some of the manifestations are common to both AEs.  
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug fever); Arthralgia (joint 
pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; 
Hypertension; Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating 
(diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); 
Vomiting or Diarrhea. 
Treatment guidelines for subjects who experience an infusion related reaction associated with administration of MK-3475. 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 
24 hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Corticosteroids 
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 two hours 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 3 toxicity despite adequate 
 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of MK-3475 with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
 
Additional pre-
medication as needed per 
treating provider’s 
discretion. 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
premedication should be permanently discontinued from 
further trial treatment. If ≥ 3 cycles of therapy was given, 
patients will go to observation, otherwise event monitoring. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment administration. If ≥ 2cycles of therapy was given, 
patients will go to observation, otherwise event monitoring. 
 
No subsequent dosing, 
discontinue the treatment. 


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9.9b 
Supportive Care Guidelines for Events of Clinical Interest and Immune-related Adverse 
Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as 
an adverse event of unknown etiology, associated with drug exposure and is consistent 
with an immune phenomenon.  irAEs may be predicted based on the nature of the  
MK-3475 compound, its mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action.  Special attention should be 
paid to AEs that may be suggestive of potential irAEs.  An irAE can occur shortly after 
the first dose or several months after the last dose of treatment.   
 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes prior to labeling an adverse event as an irAE.  
Subjects who develop a Grade 2 or higher irAE should be discussed immediately with the 
Investigator/Sponsor.   
 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in the 
table below. 
General Approach to Handling irAEs 
irAE 
Withhold/Discontinue 
MK-3475 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold MK-3475 
Consider systemic corticosteroids in 
addition to appropriate symptomatic 
treatment 
Grade 3 and Grade 4 
Withhold MK-3475 
Discontinue if unable to 
reduce corticosteroid 
dose to < 10 mg per day 
prednisone equivalent 
within 8 weeks of 
toxicity 
If ≥ 2 cycles of therapy 
was given, patients will 
go to observation, 
otherwise event 
monitoring. 
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic 
treatment.  May utilize 1 to 2 mg/kg 
prednisone or equivalent per day. 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered gradually. 
 
 


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10.0 
Adverse Event (AE) Reporting and Monitoring 
NOTE:  References to grade will always be per CTCAE throughout section 10.0. 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web 
    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.5).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
10.12 Each CTCAE term in the current version is a unique representation of a specific 
event used for medical documentation and scientific analysis and is a single 
MedDRA Lowest Level Term (LLT).  Grade is an essential element of the 
Guidelines and, in general, relates to severity for the purposes of regulatory 
reporting to NCI. 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE which is defined in the table in Section 10.4. 
10.2  
Expected vs. Unexpected Events  
• 
The determination of whether an AE is expected is based on agent-
specific information provided in Section 15.0 of the protocol and the study 
specific consent form. 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol and the study specific consent form. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 


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Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical treatment 
suggest there is evidence to indicate a causal relationship between the drug and the 
adverse event.  
 




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1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional instructions: 
1. Contact: Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
) 
2.Use MedWatch form, Form FDA 3500a, available on the FDA website at 
  
Following completion of the FDA electronic form, print for signature and submission.  
Submit to Merck Global Safety. (Attn: Worldwide Product Safety; FAX
) 
 
Mayo Clinic Cancer Center (MCCC) Institutions:  Provide copies, along with the UPIRTSO 
cover sheet, by fax (
) to the MCCC Regulatory Affairs Unit (RAU) Risk 
Information Specialist who will determine and complete IRB reporting. The RAU will submit to 
the MCCC SAE Coordinator and the MCCC IND Coordinator to determine if FDA submission is 
needed 
 
10.41 Special Situations for Expedited Reporting 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2, 3 and 4 Serious 
Adverse Events where the AE is EXPECTED. Any protocol specific reporting 
procedures MUST BE SPECIFIED BELOW and will supercede the standard 
Expedited Adverse Event Reporting Requirements.  Note:  These adverse events 
must still be reported through the routine reporting mechanism [i.e. 
Nadir/Adverse Events Form]; see footnote 1. 
 
CTCAE Category 
Adverse Event 
CTCAE Grade 
Blood and lymphatic 
system disorders 
Anemia 
3 or 4 
Investigations 
Platelet count 
decreased 
3 or 4 
Neutrophil count 
decreased 
3 or 4 
Lymphocyte count 
decreased 
3 or 4 


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MCCC Addendum 14 
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White blood cell 
decreased 
3 or 4 
1  These exceptions only apply if the adverse event does not result in hospitalization.  If 
the adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
10.5 
Other Required Reporting 
10.51 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to as 
disabilities), congenital abnormities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under an 
IND/IDE since they are considered to be a serious AE and must be reported to 
the sponsor as specified in 21 CFR 312.64(b). 
10.52 Death 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 24-
hours. 
 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal:  A disorder characterized by cessation of life during the first 
28 days of life. 
• 
Death NOS:  A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS:  A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) – Other 
(Progressive Disease)” under the system organ class (SOC) of the same 
name.  Evidence that the death was a manifestation of underlying disease 
(e.g., radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted. 
 


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10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy).  A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE need to be reported. Three options are available to 
describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy).  Second malignancies 
require ONLY routine reporting. 
10.55 Reporting of Pregnancy and Lactation to the Cancer Center Compliance 
Unit and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them), including the pregnancy 
of a male subject's female partner that occurs during the trial or within 120 days 
of completing the trial, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier.  All subjects 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 24 hours to Cancer Center Compliance Unit 
at 
 and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; 
) 
 


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10.6 
Required Routine Reporting  
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System Organ Class 
(SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Investigations 
Platelet count decreased* 
X 
X 
Neutrophil count decreased 
X 
X 
Blood and lymphatic 
system disorders 
Anemia* 
X 
X 
Gastrointestinal disorders 
# of stools 
X 
 
Diarrhea 
 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Respiratory, thoracic and 
mediastinal disorders 
Cough 
X 
X 
Dyspnea 
X 
X 
Pneumonitis 
X 
X 
Skin and subcutaneous 
tissue disorders 
Rash maculo-papular 
X 
X 
* Grading will be performed by the study statisticians at the time of analysis based on the 
CLL toxicity grading scale for blood counts in Appendix IV. CTCAE grades for platelet 
count decreased and anemia will also be recorded for reporting purposes. 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.613 Grade 5 AEs (Deaths) 
10.6131 Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
10.6132 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with a 
CTCAE type and attribution assigned. 
10.62 Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 


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11.0 
Treatment Evaluation 
Response will be evaluated after approximately 3, 6, and 12 months of single or 
combination treatment. (Note: Disease measurements obtained after the last cycle of 
single-agent therapy are set as the baseline measurements for the combination therapy 
phase.)  If the patient remains on cycles with a length of 21 days without treatment 
delays, this will be at the end of cycles 4, 9, and 17 (approximately days 84, 189, and 
357).  If the cycle length is increased due to dosing frequency changes or dose delays 
occur, the response evaluations should occur where the end of the cycles are closest to 3, 
6, and 12 months (days 92, 183, and 365), keeping in mind that this may occur before 3, 
6, or 12 months.  Response evaluation at 3, 6, and 12-month time points unless treatment 
has been stopped/completed and then the response evaluation can be performed between 
2-8 weeks after last therapy. 
 
Arm A :  CLL/SLL patients without Richter’s transformation or Hodgkin transformation 
 
Note:  For CLL patients with Richter’s transformation or Hodgkin transformation,  
see Section 11.5 (Arm A) or Section 11.6 (Arm C) for response evaluation for the 
transformed (lymphoma) phase of the disease, but their CLL phase of the disease will 
still be evaluated based on Section 11.1-4. 
 
Note: Formal response evaluation should occur at the end of 3, 6, and 12 months with 
the first response evaluation occurring at the end of cycle 4 and before the start of cycle 5 
or at the end of the cycle closest to 3 months of therapy, whichever occurs first.  
Objective status should be classified as PD vs. Not PD on cycles when a formal response 
evaluation does not occur. 
11.1 
Schedule of evaluations:  For the purposes of this study, patients should be reevaluated 
for progression during each cycle assessment during the first 3 months of therapy with 
MK3475.  After 3 months, patients who do not have evidence of PD or SD will continue 
on therapy and these patients will be evaluated for disease progression every other cycle.  
Formal response evaluation will occur at 3, 6, and 12 months since therapy start.  For 
patients who discontinued the therapy due to adverse events, but have received at least 3 
cycles of therapy and do not have evidence of PD, they should have formal response 
evaluation at about 2-8 weeks after the last dose of therapy or at the 3, 6, and 12-month 
time point since therapy start which ever occurs first.  Prior to the first formal response 
evaluation, baseline on study measurements will be used to determine disease progression 
(e.g. not cycle by cycle comparisons).  Once patients undergo formal response 
evaluation, the nadir value at either baseline or time of response evaluation will be used 
for evaluating future disease progression. In addition to a baseline scan, confirmatory 
scans should also be obtained as needed to document objective response at sites of  
non-palpable lymphadenopathy or organomegaly as indicated in Section 4 or as needed 
clinically. 
NOTE: Information from CT scans is not considered in the standard classification of 
response. 
11.2 
Definitions 
The NCI Working Group criteria (Hallek, 2008) will be used to assess response to 
therapy.  
11.21 COMPLETE RESPONSE (CR) requires all of the following for a period of at 
least  


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2 months.  The first formal response evaluation for CR should occur no sooner 
than the end of cycle 3. 
11.211 Absence of lymphadenopathy (e.g. lymph nodes >1.5 cm) by physical 
examination. 
11.212 No hepatomegaly or splenomegaly by physical examination. 
11.213 Absence of constitutional symptoms. 
11.214 CBC demonstrating: 
• 
Neutrophils >1500/ul. 
• 
Platelets >100,000/ul (untransfused). 
• 
Hemoglobin >11.0 gm/dl (untransfused). 
• 
Peripheral blood lymphocytes <4000/uL. 
 
Note: Patients who fulfill all criteria for a CR but who have a persistent 
anemia, thrombocytopenia, or neutropenia related to drug toxicity rather 
than residual CLL will be classified as CR with incomplete marrow 
recovery (CRi) according to the international criteria (Hallek, 2008). 
11.215 Bone marrow aspirate and biopsy should be performed  at the end of the 
cycle closest to 6 months or 12 months of therapy or at the same time for 
response evaluation for patients who received ≥ 3 cycles of treatment and 
are off therapy due to AE (see note in section 4.0), which ever occurred 
sooner.    The marrow sample should ideally be at least normocellular 
with <30% of nucleated cells being lymphocytes.  Samples are to be 
analyzed by a pathologist and the presence or absence of nodules noted.  
Repeat bone marrow aspirate and biopsy are not necessary to document 
sustained CR. 
 
NOTE:  Patients who fulfill all criteria for a CR but who have 
hypocellular marrow will be classified as a CR with incomplete 
marrow recovery (CRi). 
 
In a subset of patients who are otherwise in a complete response, bone 
marrow nodules can be identified histologically.  In such cases, special 
stains will be performed to determine whether such nodules represent 
“regenerative nodules” or residual “clonal nodules”.  The presence of 
regenerative nodules is consistent with CR while the presence of residual 
clonal nodules will be classified as an nPR (nodular PR) which is a sub-
classification of PR.   Per the PR criteria, patients must fulfill one or 
more of the blood count parameters (Section 11.224, 11.225, 11.226) but 
are not required to meet all 3 of these conditions. 
11.216 Patients who have clinical and laboratory evidence of CR but who have 
not yet had a bone marrow biopsy to distinguish between CR and nPR 
will be classified as having a Complete Clinical Response (CCR) until 
the marrow biopsy is obtained.   Patients must meet all of the blood 
count parameters listed in section 11.214. 
11.217 In some settings MRD assays may be considered as a surrogate of 
response as discussed in section 11.3.  No other laboratory assays (e.g., 
quantitative immunoglobulins) will be used currently as an index for 


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response but will be recorded for clinical correlations. 
11.218 For patients whose only measurable disease at the time of enrollment is 
on CT scan (i.e. SLL with no palpable nodes), a CT scan showing 
absence of lymphadenopathy (e.g. lymph nodes >1.5 cm) is required 
before classifying patients a CR. 
11.22 PARTIAL RESPONSE (PR) requires the patient exhibits at least two of the 
features in Sections 11.221, 11.222, and 11.223 below (if abnormal prior to 
therapy) as well as one or more of the remaining features (Sections 11.224, 
11.225, 11.226) for at least 2 months.  In addition to the parameters listed below, 
the presence or absence of constitutional symptoms will be recorded.  .   
11.221 ≥50% decrease in peripheral blood lymphocyte count from the 
pretreatment baseline value. 
11.222 ≥50% reduction in the sum of the products of the maximal perpendicular 
diameters of the largest measured node or nodal masses in the right and 
left cervical, axillary, and inguinal lymph node regions on physical 
examination.  
11.223 ≥50% reduction in size of liver and/or spleen as measured by physical 
exam noting the maximal distance below the respective costal margins of 
palpable hepatosplenomegaly during rest.   
11.224 Neutrophils >1500/ul or 50% improvement over baseline. 
11.225 Platelets >100,000/ul or 50% increase over baseline. 
11.226  Hemoglobin >11.0 gm/dl or 50% increase over baseline without 
transfusions. 
11.227 For patients whose only measurable disease at the time of enrollment is 
on CT scan (i.e. SLL with no palpable nodes), a CT scan demonstrating 
> 50% reduction of target nodes enlarged at baseline is required before 
classifying patients a PR. 
11.228 For patients whose only measurable disease at the time of enrollment is 
on CT scan (i.e. SLL with no palpable nodes), a CT scan is required 
before classifying patients PR. 
11.23 PROGRESSION (PD):   
11.231 Patients will receive protocol therapy unless they have evidence of 
disease progression according to the NCI criteria (Hallek, Cheson et al. 
2008) as evidenced by: ≥ 50% increase in the sum of the products of at 
least 2 lymph nodes on 2 consecutive determinations 4 weeks apart (at 
least one node must be ≥2 cm) or the appearance of new palpable lymph 
nodes >1.5 cm not due to a tumor flare for lasting more than 4 weeks.  
Enlargements or the appearance of new nodes due to a tumor flare do 
NOT qualify as progression.   
11.232 ≥ 50% increase in the size of the liver and/or spleen as determined by 
measurement below the respective costal margin on 2 consecutive 
determinations 4 weeks apart and with a minimum of a ≥ 2 cm increase 
in size from baseline; or appearance of hepatomegaly or splenomegaly 
which was not previously present at baseline and not due to a tumor flare 
on 2 consecutive determinations 4 weeks apart 


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11.233 Transformation to a more aggressive histology (e.g. Richter’s 
transformation). 
 
NOTE:  If a patient develops DLBCL at any time, it will be considered 
progressive disease.   If the patient develops any other hematological 
malignancy while on study, it will not be considered progressive disease. 
11.234 ≥ 50% increase in the absolute number of circulating lymphocytes NOT 
due to infection or tumor flare or reactive process to complications or 
potential clinical response associated with novel therapies for at least 2 
different time points at least 4 weeks apart (taking as reference for 
progressive disease the smallest absolute lymphocyte count recorded 
since the treatment started).  The absolute lymphocyte count must be at 
least 5000/mm3 to qualify as potential disease progression. The increase 
of absolute lymphocyte count also has to be associated with increase of 
either lymph node or spleen/liver size for at least 2 different occasions at 
least 4 weeks apart. 
11.235 In the absence of progression as defined by 1, 2, 3, or 4 above, the 
presence of a ≥2 g/dl decrease in HGB, or ≥50% decrease in platelet 
count, or absolute neutrophil count will NOT exclude a patient from 
continuing the study.  Work-up of such decreases to exclude auto-
immune hemolytic anemia, pure red cell aplasia, or idiopathic 
thrombocytopenic purpura (ITP) should be considered. However, if it is 
confirmed that ≥2 g/dl decrease in HGB, or ≥50% decrease in platelet 
count is due to CLL progression in marrow, this is considered as 
confirmed CLL PD. 
11.236 In the case where progression is confirmed on at least 2 occasions at least 
4 weeks apart, the objective status will be entered as unconfirmed 
progression (uPD) on the measurement form at the time this criteria is 
first met.  Once this criteria is confirmed at least 4 weeks later, the 
objective status will be entered as PD.  If confirmed, the date of first 
evidence of progression (date of first uPD) will be considered the 
progression date (and should be entered on the event monitoring form).   
11.237 Patients whose only evidence of disease recurrence is by sensitive 
evaluation of MRD will NOT be considered PD. 
11.24 STABLE DISEASE (SD): Patients who do not meet criteria for CR, CRi, nPR, 
CCR, PR, or PD will be classified as having “stable disease”.  The first formal 
response evaluation should occur no sooner than the end of cycle 3.   
11.25 Not PD:   The patient was evaluated for progression only this cycle and a formal 
response evaluation did not occur.  The patient did not meet the criteria for 
progression per section 11.23.   
Note:  Formal response evaluation should occur at 3, 6, and 12 months with the 
first response evaluation occurring at the end of cycle 4 or at the end of the cycle 
closest to 3 months of therapy, whichever occurred earlier.  For patients who 
have received more than 2 cycles of treatment and off therapy due to AE, they 
should have formal response evaluation between 2-8 weeks from the last therapy 
as long as they do not have evidence of PD. Objective status should be classified 
as PD vs. Not PD on cycles when a formal response evaluation does not occur.   


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11.3  
EVALUATION OF MINIMAL RESIDUAL DISEASE (MRD):  An important aspect of 
this trial is evaluation of minimal residual disease using a sensitive flow cytometry 
method capable of detecting approximately 1 CLL cell per 10,000 leukocytes following 
induction. 
An International, standardized approach for flow cytometric evaluation of residual 
disease in patients with CLL was recently developed (Rawstron, Villamor et al. 2006). 
This approach reliably detects residual CLL B-cells at the level of 1 leukemic cell per 
10,000 leukocytes.  Notably, analysis of peripheral blood was equally or more sensitive 
to marrow in 92% of samples except when patients had received treatment with 
monoclonal antibodies within 3 months of evaluation. 
 
This approach uses a pre-antibody ammonium chloride red cell lysis approach to separate 
peripheral blood white blood cells from RBCs followed by staining of 1-2 x 106 
leukocytes with a panel of antibodies for flow cytometry analysis. For each test, 300,000 
to 500,000 events were collected to ensure the desired sensitivity of the assay.    
 
While the 4 color based strategy was the standard proposed by the international group, 5- 
to even 8-color flow cytometry based assays are being used in many laboratories and are 
expected to have a similar degree of sensitivity (level of 1 leukemic cell per 10,000 
leucocytes) while enhancing the accuracy of the assay.  
 
These assessments for MRD in the present study will be conducted in the Mayo Clinic’s 
campus in Rochester Department of Hematopathology under the direction of 
 
 using a flow cytometry strategy able to detect residual leukemia at the level of 1 
leukemic cell per 10,000 leukocytes in accord with the International Standard (Rawstron, 
Villamor et al. 2006).  The antibody panel includes:  CD45, CD19, CD20, CD5, and anti-
kappa and anti-lambda immunoglobulin light chains.  For each test, 300,000 to 500,000 
events are collected to ensure the desired sensitivity of the assay.    
 
All patients with evidence of response (CR, CRi, CCR, nPR) will undergo assessment of 
MRD using sensitive flow cytometry at the completion of MK3475 therapy. If bone 
marrow samples are available, marrow MRD testing is preferred. 
 
 


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11.4 
Summary Definition of objective response for patients with B–CLL/SLL 
 
 
CCR1 
CR2, 9 
CRi3, 9 
nPR4, 9 
PR5 
PD6 
Physical Exam  
 
Nodes7 
None 
None 
None 
None 
≥50%  
≥50% , new 
nodes 
Liver/spleen8 
Not 
palpable 
Not palpable 
Not palpable 
Not palpable 
≥50%  
≥50% , newly 
palpable 
Symptoms 
None 
None 
None 
None 
N/A 
N/A 
PERIPHERAL BLOOD 
 
ANC 
>1500/µL 
>1500/µL 
See footnote 3 
>1500/µL or 
>50% 
improvement 
from baseline 
>1500/µL or >50% 
improvement from 
baseline 
See footnote 6 
Platelets 
>100,000/ 
µL 
>100,000/µL 
See footnote 3 
>100,000/µL or 
>50% 
improvement 
from baseline 
>100,00/µL or >50% 
improvement from 
baseline 
Decrease of ≥ 50% 
from baseline 
secondary to CLL 
See footnote 6 
Hemoglobin 
>11.0 g/dL 
without 
transfusion 
>11.0 g/dL 
without 
transfusion 
See footnote 3 
>11.0 g/dL or 
>50% 
improvement 
from baseline 
without 
transfusion 
>11.0 g/dL or >50% 
improvement from 
baseline without 
transfusion 
Decrease ≥ 2g/dL 
from baseline 
secondary to CLL 
See footnote 6 
Lymphocytes 
<4000/µL 
<4000/µL 
<4000/µL 
<4000/µL 
≥50%  
≥50%  to at least 
5,000/µL due to 
clear progression, 
not other reasons 
BONE 
MARROW 
N/A 
Normocellular3
; <30% 
lymphocytes; 
no nodules 
<30% 
lymphocytes; no 
nodules 
<30% 
lymphocytes; 
bone marrow 
nodules4 
N/A 
N/A 


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1. 
Clinical complete response (CCR) requires fulfillment of all physical exam and peripheral blood criteria as noted in the table above.  No 
bone marrow biopsy is required to call a patient a CCR; however, patients should have a bone marrow around the same time of the formal 
response evaluation as instructed in the test schedule to confirm CR.   
2. 
Complete response (CR) requires fulfillment of all physical exam and peripheral blood criteria for a duration of ≥2 months.  A bone 
marrow aspirate and biopsy are required to document the response as a complete within one month of the formal response evaluation where 
clinical and laboratory evidence of complete response was first seen (see Section 11.21).   
3.      Patients who fulfill all criteria for a CR but who have a persistent anemia, thrombocytopenia, or neutropenia related to drug toxicity rather 
than residual CLL or have hypocellular marrow will be classified as CR with incomplete marrow recovery (CRi).   
4. 
Nodular partial response (nPR) is essentially a patient in who it appeared that CR had been obtained but nodules are present in the bone 
marrow.  It requires fulfillment of all physical exam and lymphocyte criteria for CR; however, when the bone marrow is done to confirm CR, 
nodules of malignant lymphocytes are found.  Patients must fulfill one or more of the blood count parameters (ANC, Platelets, Hemoglobin) but 
are not required to meet all 3 of these conditions. See Section 11.215 regarding the distinction between clonal and regenerative nodules.  
5. 
Partial response (PR) requires fulfillment of at least two of the above-noted decrease in circulating lymphocytes, regression in adenopathy 
and regression in hepatosplenomegaly, and at least one other parameter listed above for a duration of ≥ 2 months.  See Section 11.22. 
6. 
Progression:  Fulfilling the criteria as noted in section 11.23.  Prior to the formal response evaluation, baseline on study measurements will 
be used to determine disease progression (e.g. not cycle by cycle comparisons).  Once patients undergo formal response evaluation, the nadir value 
at either baseline or time of response will be used for evaluating future disease progression. In the absence of other indices of clinical progression, 
the presence of a ≥2 g/dL decrease in hemoglobin or a ≥50% decrease in platelet count and/or absolute neutrophil count will not exclude a patient 
from continuing on the study. Although not mandatory, bone marrow aspirate and biopsy are strongly encouraged to better define the cause of the 
suppressed counts (i.e. treatment- versus disease-related).   In case worse cytopenia is secondary to CLL marrow progression, this is confirmed 
PD. In the case where progression due to nodal progression is confirmed on at least 2 occasions at least 4 weeks apart, the objective status will be 
entered as unconfirmed progression (uPD) on the measurement form at the time this criteria is first met.  Once this criteria is confirmed at least 4 
weeks later, the objective status will be entered as PD.  If confirmed, the date of first evidence of progression (date of first uPD) will be considered 
the progression date (and should be entered on the event monitoring form).   
7. 
Measurement of lymphadenopathy will be determined on physical exam by adding the sum of the products of the maximal perpendicular 
diameters of measured lesion(s).  No simultaneous increase in the size of any lesions or the appearance of any new lesions may occur for more 
than 2 consecutive cycles.  Minor fluctuations are acceptable as long as they don’t exceed 50% of previous measurement.  However, if they do 
exceed 50% of the previous measurement it should be held for 2 consecutive cycles to rule out the possibility of nodes that wax and wane.  For 
purposes of determining CCR and nPR, all nodes on physical exam need to be ≤1.5 cm in maximal dimension or documented to be free of CLL by 
biopsy. NOTE: Information from CT scans regarding lymphadenopathy is not considered in the standard classification of response with the 
exception of the patients fitting criteria of section 11.218 and 11.228. 
8. 
Measurement of hepatosplenomegaly will be determined by noting the maximal distance below the respective costal margins of palpable 
hepatosplenomegaly during rest (e.g., not during deep inspiration). NOTE: Information from CT scans regarding hepatosplenomegaly is not 
considered in the standard classification of response with the exception of the patients fitting criteria of section 11.218 and 11.228. 


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Note :  See Section 11.7 for patients on Arm B with Waldenstrom macroglobulinemia 
11.5 
Arm B: Low grade NHL patients  
Response Considerations 
 
Definitions for clinical response for patients with lymphoma are from the Cheson et al. 
Revised Response Criteria for Malignant Lymphoma (Cheson, Pfistner et al. 2007).  
Lymph node measurements should be taken from the CT portion of the PET/CT, or MRI 
scans, or dedicated CT scans where applicable.  Measurement of lymphadenopathy will 
be determined by adding the sum of the products of the maximal perpendicular diameters 
of measured lesions (SPD).  Measurable extranodal disease should be assessed in a 
manner similar to that for nodal disease. For these recommendations, the spleen is 
considered nodal disease. Disease that is only assessable (eg, pleural effusions, bone 
lesions) will be recorded as present or absent only, unless, while an abnormality is still 
noted by imaging studies or physical examination, it is found to be histologically and 
pathologically negative.  Disease assessable by physical exam only (e.g. skin lymphoma) 
will be recorded as either measurable diseases using targeted lesions or photography at 
the baseline and subsequent visits for response assessment. 
 
Response is based on CT alone or the CT component of PET/CT or MRI where 
applicable and the PET.  
 
PET/CT scans are required at baseline for all Follicular lymphoma grade 3  
 
Follicular lymphoma grade 3 PET scans are required at response assessments for these 
patients.  These patients should be followed by the FDG-avid or PET positive criteria 
(part a).     
 
Follicular lymphoma grade 1 or 2 and marginal zone lymphoma:  Response will be 
determined by CT (PET/CT or dedicated CT).  These patients should be followed by the 
variably FDG-avid or PET negative criteria (part b). 
 
Waldenstrom macroglobulinemia:  For patients with Waldenstrom macroglobulinemia, 
response will be assessed according to Section 11.6. 


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Response criteria, modified from Cheson et al. 2007.  
Response 
Category 
Definition 
Nodal Masses1 
Spleen, liver 
Bone Marrow 
CR 
Disappearance of all 
evidence of disease. 
a) FDG-avid or PET positive 
prior to therapy: Mass of any 
size permitted if PET negative  
b) Variably FDG-avid or PET 
negative: Regression to normal 
size on CT or resolve of 
measurable disease by physical 
exam only (e.g. skin 
lymphoma) 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate 
by morphology, 
immunohistoche
mistry should be 
negative 
PR 
Regression of 
measurable disease 
and no new sites 
≥50% decrease in SPD of up to 
6 largest dominant masses or 
≥50% decrease of other 
measurements (e.g. skin 
lymphoma ) only measurable 
by physical exam; no increase 
in size of other nodes 
and a) or b): 
a) FDG-avid or PET positive 
prior to therapy: one or more 
PET positive at previously 
involved sites 
b) Variably FDG-avid or PET 
negative: regression on CT 
≥50% 
decrease in 
SPD of 
nodules (for 
single nodule 
in greatest 
transverse 
diameter); no 
increase in 
size of liver 
or spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
a) FDG-avid or PET positive 
prior to therapy: PET positive 
at prior sites of disease and no 
new sites on CT or PET 
b) Variably FDG-avid or PET 
negative: no change in size of 
previous lesions on CT 
 
 
Relapse/ 
Progressive 
disease 2 
Any new lesion or 
increase by ≥50% of 
previously involved 
sites from nadir 
Appearance of a new lesion(s) 
> 1.5 cm in any axis, ≥50% 
increase from nadir in SPD of 
more than one node, or ≥50% 
increase in longest diameter of 
a previously identified node > 1 
cm in short axis not due to 
tumor flare and persistent for 4 
weeks apart. 
Lesions PET positive if FDG-
avid lymphoma or PET positive 
prior to therapy persistent for 4 
weeks apart 
> 50% 
increase from 
nadir in the 
SPD of any 
previous 
lesions not 
due to tumor 
flare and 
persistent for 
4 weeks 
apart. 
 
New or recurrent 
involvement 
Abbreviations: CR, complete response; FDG, [18F]fluorodeoxyglucose; PET, positron emission 
tomography; CT, computed tomography; PR, partial response; SPD, sum of the product of the diameters; 
STAB, stable disease; PD, progressive disease. 
 


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1  Patients will be assessed by part a or part b as specified in section 11.5. For patients with predominant 
skin lymphoma, skin disease should be recorded as photograph or measurable diseases as targeted lesions.  
Please refer to published guideline{Olsen, 2011 #547}. 
2 In the case where progression is confirmed on at least 2 occasions at least 4 weeks apart, the objective 
status will be entered as unconfirmed progression (uPD) on the measurement form at the time this 
criterion is first met.  Once this criterion is confirmed at least 4 weeks later, the objective status will be 
entered as PD.  If confirmed, the date of first evidence of progression (date of first uPD) will be 
considered the progression date (and should be entered on the event monitoring form). 
 
 
11.51 Complete Response (CR).  The designation of CR requires all of the following: 
11.511 Complete disappearance of all detectable clinical evidence of disease and 
definitely disease-related symptoms if present before therapy.  
11.512 Patients will be assessed by part a or part b as specified in section 11.5. 
a)   In patients with pretreatment PET scan or when the PET scan was 
positive before therapy, a post-treatment residual mass of any size is 
permitted as long as it is PET negative. 
 
b)  In patients without a pretreatment PET scan, or if a pretreatment PET 
scan was negative, all lymph nodes and nodal masses must have 
regressed on CT to normal size (≤1.5 cm in their greatest transverse 
diameter for nodes > 1.5 cm before therapy). Previously involved nodes 
that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their 
short axis before treatment must have decreased to ≤1.0 cm in their short 
axis after treatment.  For patients with only skin involvement, these same 
criteria apply to skin lesions photographed and measured with a ruler 
with images maintained in the medical record. 
 
c) Resolve of measurable disease by physical exam only (e.g. skin 
lymphoma). 
11.513 The spleen and/or liver, if considered enlarged before therapy on the 
basis of a physical examination or CT scan, should not be palpable on 
physical examination and should be considered normal size by imaging 
studies, and nodules related to lymphoma should disappear. However, 
determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use 
of hematopoietic growth factors, or causes other than lymphoma.  
Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have 
decreased in size. 
11.514 If the bone marrow was involved by lymphoma before treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy. The biopsy 
sample on which this determination is made must be adequate (with a 
goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry but that demonstrates a small 
population of clonal lymphocytes by flow cytometry will be considered a 
CR until data become available demonstrating a clear difference in 
patient outcome.  


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11.52 Criteria for Partial Response (PR). The designation of PR requires all of the 
following: 
11.521 At least a 50% decrease in sum of the product of the diameters (SPD) of 
up to six of the largest dominant nodes or nodal masses. These nodes or 
masses should be selected according to all of the following:  
• 
they should be clearly measurable in at least 2 perpendicular 
dimensions 
• 
if possible they should be from disparate regions of the body 
• 
they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved or ≥.50% decrease of other 
measurements (e.g. skin lymphoma ) only measurable by physical 
exam {Olsen, 2011 #547} 
• 
≥50% decrease of other measurements (e.g. skin lymphoma ) only 
measurable by physical exam 
11.522 No increase should be observed in the size of other nodes, liver, or 
spleen. 
11.523 Splenic and hepatic nodules must regress by 50% in their SPD or, for 
single nodules, in the greatest transverse diameter.  
11.524 With the exception of splenic and hepatic nodules, involvement of other 
organs is usually assessable and no measurable disease should be present. 
11.525 Bone marrow assessment is irrelevant for determination of a PR if the 
sample was positive before treatment. However, if positive, the cell type 
should be specified (eg, large-cell lymphoma or small neoplastic B cells). 
Patients who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial 
responders.  
When the bone marrow was involved before therapy and a clinical CR 
was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
11.526 No new sites of disease should be observed. 
11.527 Patients will be assessed by part a or part b as specified in section 11.5. 
a)  For patients with pretreatment PET scan or if the PET scan was 
positive before therapy, the post-treatment PET should be positive in at 
least one previously involved site. 
 
In patients with follicular lymphoma or mantle-cell lymphoma, a PET 
scan is only indicated with one or at most two residual masses that have 
regressed by more than 50% on CT; those with more than two residual 
lesions are unlikely to be PET negative and should be considered partial 
responders.b)  For patients without a pretreatment PET scan, or if a 
pretreatment PET scan was negative, CT criteria should be used (except 
in patients with only skin involvement where skin lesions are 
photographed and measured with a ruler). 
11.53 Criteria for Stable Disease (STAB) 
11.531  A patient is considered to have SD when he or she fails to attain the 
criteria needed for a CR or PR (see above), but does not fulfill those for 


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progressive disease (see below).  
11.532  Patients will be assessed by part a or part b as specified in section 11.5. 
a)  The PET should be positive at prior sites of disease with no new areas 
of involvement on the post-treatment CT or PET.  
b)   For patients without a pretreatment PET scan or if the pretreatment 
PET was negative, there must be no change in the size of the previous 
lesions on the post-treatment CT scan (or on ruler measurements for 
patients with only skin involvement). 
11.54 Relapsed Disease (after CR)/Progressive Disease (after PR, SD): Lymph 
nodes should be considered abnormal if the long axis is more than 1.5 cm 
regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it 
should only be considered abnormal if its short axis is more than 1.0. Lymph 
nodes ≤1.0 x ≤1.0 cm will not be considered as abnormal for relapse or 
progressive disease.  
11.541 Appearance of any new lesion more than 1.5 cm in any axis during or at 
the end of therapy for at least 4 weeks apart, even if other lesions are 
decreasing in size. Increased FDG uptake in a previously unaffected site 
should only be considered relapsed or progressive disease after 
confirmation with other modalities to be persistent. In patients with no 
prior history of pulmonary lymphoma, new lung nodules identified by CT 
are mostly benign. Thus, a therapeutic decision should not be made solely 
on the basis of the PET without histologic confirmation.  Tumor flare 
reactions should be ruled out. 
11.542 At least a 50% increase from nadir in the SPD of any previously involved 
nodes, or in a single involved node, or the size of other lesions (eg, 
splenic or hepatic nodules). To be considered progressive disease, a 
lymph node with a diameter of the short axis of less than 1.0 cm must 
increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the 
long axis. The above changes have to be persistent for 4 weeks apart not 
due to tumor flare reaction. 
11.543 At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis. The above changes have 
to be persistent for 4 weeks apart.  Tumor flare reactions should be ruled 
out. 
11.544  If patient is being assessed by part a as specified in section 11.5:   
Lesions should be PET positive if  observed in a typical FDG-avid 
lymphoma or the lesion was PET positive before therapy unless the lesion 
is too small to be detected with current PET systems (< 1.5 cm in its long 
axis by CT).  
11.545 Transformation to a more aggressive histology 
11.546 In the case where progression is confirmed on at least 2 occasions at least 
4 weeks apart, the objective status will be entered as unconfirmed 
progression (uPD) on the measurement form at the time this criterion is 
first met.  Once this criterion is confirmed at least 4 weeks later, the 
objective status will be entered as PD.  If confirmed, the date of first 
evidence of progression (date of first uPD) will be considered the 
progression date (and should be entered on the event monitoring form).   


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11.6  
Arm C and Arm A for CLL patients with Richter’s transformation 
Response Considerations 
 
Schedule of Evaluations:  PET/CT scans are required at baseline for all patients. In 
addition to a baseline PET/CT scan, scans should also be obtained to assess clinical 
responses after 3, 6, and 12 months of therapy or when it is clinically needed by treating 
physician.  
Definitions for clinical response for patients with lymphoma are from the recently revised 
Cheson’s et al criteria published in 2014, derived from the original criteria published in 
2007. (Cheson et al, 2014)(Cheson et al, 2007). Lymph node measurements should be 
taken from the CT portion of the PET/CT, or other dedicated CT scans where applicable.  
Measurement of lymphadenopathy for purposes of assessing for PR will be determined 
by adding the sum of the products of the maximal perpendicular diameters of measured 
lesions (SPD).  The PPD of a single node is sufficient to evaluate for PD (see Table 
11.61).  Measurable extranodal disease should be assessed in a manner similar to that for 
nodal disease. For these recommendations, the spleen is considered nodal disease. 
Disease that is only assessable (eg, pleural effusions, bone lesions) will be recorded as 
present or absent only, unless, while an abnormality is still noted by imaging studies or 
physical examination, it is found to be histologically and pathologically negative. 
 
Response is based on PET/CT based on the revised 2014 Lugano Classification. (Cheson 
et al, 2014). 
 
Progressive disease is based on either PET-CT based (PMD) or CT based (PD) response 
criteria if PET is not available.  PET confirmation of progressive disease is per physician 
discretion. 








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signs of WM 
Progressive disease 1 
A 25% increase from nadir in serum monoclonal IgM by protein 
electrophoresis confirmed by a second measurement 4 weeks apart or 
progression of clinically significant findings as a result of disease (i.e., 
anemia, thrombocytopenia, leukopenia, bulky adenopathy/organomegaly) 
or symptoms attributable to WM (unexplained recurrent fever 38.4°C, 
drenching night sweats, 10% body weight loss, hyperviscosity, 
neuropathy, symptomatic cryoglobulinemia, or amyloidosis) 
 
Transformation to a more aggressive histology 
NOTE. Data from Kimby E, Treon SP, Anagnostopoulos A, et al. Clin Lymphoma 
Myeloma 6:380-383, 2006. 
 
1  In the case where progression is confirmed on at least 2 occasions at least 4 weeks 
apart, the objective status will be entered as unconfirmed progression (uPD) on the 
measurement form at the time this criteria is first met.  Once this criteria is confirmed at 
least 4 weeks later, the objective status will be entered as PD.  If confirmed, the date of 
first evidence of progression (date of first uPD) will be considered the progression date 
(and should be entered on the event monitoring form).   


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12.0 
Descriptive Factors 
12.1 
CLL Patients 
12.11 Rai Stage:  0 vs. 1 vs. 2 vs. 3 vs. 4. 
12.12 CD38+ expression:  Positive (≥30%) vs. negative (<30%). 
12.13 Chromosomal anomalies as detected by FISH:  13q- vs. 12+ vs. 11q- vs. 17p- vs. 
other abnormality vs. normal karyotype. 
12.14 IGHV mutation status:  Mutated (≥2%) vs. unmutated (<2%) vs. indeterminate.  
12.15 ZAP-70 expression:  Positive (≥20%) vs. negative (<20%).  
12.16 CD49d expression:  Positive (≥45%) vs. negative (<45%). 
12.17 Richter transformation: yes vs. no. 
12.18 Hodgkin transformation: yes vs. no. 
12.19a Prior Ibrutinib therapy: yes or  no; if yes, progressed on Ibrutinib: yes or no 
12.19b Prior Idelalisib therapy: yes or no; if yes, progressed on Idelalisib: yes or no 
12.2 
NHL patients 
12.21  Histology category: Follicular Lymphoma vs. Lymphoplasmacytic Lymphoma 
vs. Marginal zone lymphoma. 
12.22 Prior Anti-PD-1 or Anti PDL-1 agent: Yes vs. No. 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
NOTE: Per addendum 3, for patients with Richter’s transformation, treatment and follow-
up decision will be based on the Richter’s response criteria. 
13.1 
Arm A and Arm C: If the patient develops progressive disease (not tumor flare) at any 
time while on single-agent (MK-3475) therapy, or has stable disease without partial 
remission at the response evaluation at months 3 of the single-agent (MK-3475) therapy, 
a commercially available signal inhibitor can be added to MK-3475 (remain at the dose 
200 mg IV every 3 weeks).  If the patient develops PMD/PD at any time during active 
treatment with the combination of MK-3475 and a signal inhibitor or patient refuses all 
further study participation including refusal of observation, study treatment will be 
discontinued and the patient will go directly to EVENT MONITORING. Refer to Section 
4.0 for required tests at PMD/PD. Patients will then be followed in event monitoring per 
Section 18.0.  
13.2 
Arm B : If the patient develops PD at any time during active treatment or patient refuses 
all further study participation including refusal of observation, study treatment will be 
discontinued and the patient will go directly to EVENT MONITORING. Refer to Section 
4.0 for required tests at PD. Patients will then be followed in event monitoring per 
Section 18.0. 
13.3 
Patients not progressing on active treatment and tolerating the therapy will continue 
treatment per protocol for 12 months. If patient is continuing to benefit from MK-3475 
treatment after 12 months, they may continue to receive treatment up to 24 months at 
investigator/sponsor discretion.  


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13.4 
Observation:  During observation patients will be seen every 3 months according to the 
test schedule in Section 4.0 for up to one year. When a subject discontinues treatment, all 
applicable activities scheduled for the final trial visit should be performed at the time of 
discontinuation.  Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 10.0 - Assessing and Recording Adverse Events.  
Patients will discontinue study treatment and go to observation for the following reasons:  
• Completion of 12 months or more therapy of MK3475 or combination treatment as 
determined by investigator/sponsor discretion 
• An unacceptable adverse event that occurs after the patient received at least 2 cycles 
of treatment, which in the opinion of the Investigator, precludes further trial 
participation. 
13.5 
Event Monitoring:  Patients will enter event monitoring for the following reasons: 
• 
If the patient develops evidence of PMD/PD (For CLL Arm A and C: PMD/PD on 
combination therapy; For B-NHL Arm B: PD on MK-3475 single therapy) during 
treatment or OBSERVATION by examination, blood counts, or imaging as defined 
in Sections 11.23, 11.4, 11.54 and 11.61, they will be considered to have progressed 
and will enter EVENT MONITORING. Refer to Section 4.0 for required tests at 
PMD/PD.  
 
NOTE: Patients whose only evidence of disease recurrence is by sensitive evaluation of 
MRD will continue under OBSERVATION in accord with standard clinical 
practice and will NOT be considered PD. 
 
• 
Subsequent treatment for CLL or NHL 
• 
Failure to return for an evaluation during OBSERVATION  
• 
Patient refusal of further study treatment or noncompliance  
• 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment  
• 
The Investigator withdraws the patient in the patient’s best interests  
• 
Administrative reasons (e.g., the patient is transferred to hospice care)  
• 
Pregnancy  
• 
An unacceptable adverse event that occurs during cycles 1-2 
 
Note: When a subject discontinues treatment, all applicable activities scheduled for the 
final trial visit should be performed at the time of discontinuation.  Any adverse events 
which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 10.0 -Assessing and 
Recording Adverse Events 
13.6 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient will go directly to the event-monitoring phase of the study: 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 


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13.7 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study.  
13.8 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 


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14.0 
Body Fluid Biospecimens   
14.1  
Summary Table of Research Blood and Body Fluid Specimens to Be Collected for this Protocol 
14.11 Samples collected for correlative studies for patients on single-agent MK-4375 therapy for B-NHL and CLL arm (all three 
arms) 
 
Correlative 
Study 
(Section 
for more 
information
) 
Mandator
y or 
Optional 
Blood 
or Body 
Fluid 
being 
Collecte
d 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Basel
ine  
Prior to 
cycle 
22  
Prior to 
cycle 
32  
At 3 
month 
visit2 
At 6 
and 12 
month 
visit2 
At 18 and 
24   
month 
visit2 
At Disease 
 Progression 
Bone 
marrow 
aspirate 
Mandator
y 
Bone 
marrow 
aspirate 
ACD 
(yellow top) 
6 mL 
(1 tube) 
X1 
 
 
 
X1 
 
 
Peripheral 
Blood 
Mandator
y 
Whole 
blood 
EDTA 
(purple top) 
10ml 
(1 tube) 
X 
X 
X 
X 
X 
X 
X 
Peripheral 
Blood 
Mandator
y 
Whole 
blood 
Heparin 
(green top) 
10ml 
(6 tubes) 
X 
X 
X 
X 
X 
X 
X 
Peripheral 
Blood 
Mandator
y 
Whole 
blood 
No 
anticoagulan
t (red top) 
10 ml 
(1 tube) 
X 
X 
X 
X 
X 
X 
X 
1. Only obtained when the clinical bone marrow is needed. Bone marrow samples can be collected ≤ 90 days prior to registration.  If bone 
marrow was performed prior to consenting the patient for this study, a repeat bone marrow is not required to obtain the research aspirate 
sample at baseline. 
2. - 2 days to +7, the 18 and 24 month blood samples are only required for patients who continue therapy beyond 12 months 
 


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14.12  Samples collected for correlative studies for CLL patients on combination therapy of a signal inhibitor (Ibrutinib or 
Idelalisib) with MK-3475 (CLL Arm A and C only) 
 
 
Correlative 
Study 
(Section for 
more 
information
) 
Mandato
ry or 
Optional 
Blood or 
Body 
Fluid 
being 
Collecte
d 
Type of 
Collection 
Tube (color 
of tube top) 
Volume 
to collect 
per tube 
(# of 
tubes to 
be 
collected) 
Prior 
to 2nd 
cycle 
of the 
combi
nation 
therap
y2  
 
Prior to 
3rd 
cycle 
of the 
combin
ation 
therapy
2  
At 3 
month 
visit of 
the 
combinat
ion 
therapy2 
 
At 6 and 
12 
month 
visit of 
the 
combinat
ion 
therapy2 
 
At 18 and 
24 month 
visit of 
the 
combinati
on 
therapy2  
 
At 
Disease 
Progres
sion 
 
Bone 
marrow 
aspirate 
Mandato
ry 
Bone 
marrow 
aspirate 
ACD 
(yellow 
top) 
6 mL 
(1 tube) 
 
 
 
 
X1 
 
 
Peripheral 
Blood 
Mandato
ry 
Whole 
blood 
EDTA 
(purple 
top) 
10ml  
(1 tube) 
X 
X 
X 
X 
X 
X 
Peripheral 
Blood 
Mandato
ry 
Whole 
blood 
Heparin 
(green top) 
10ml 
(6 tubes) 
X 
X 
X 
X 
X 
X 
Peripheral 
Blood 
Mandato
ry 
Whole 
blood 
No 
anticoagula
nt (red top) 
10 ml 
(1 tube) 
X 
X 
X 
X 
X 
X 
1 Only obtained when the clinical bone marrow is needed.  
2 Days to +7, the 18 and 24 month blood samples are only required for patients who continue therapy beyond 12 month 
 
 
 


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14.2  
Collection and Processing  
Processing for the Blood and Marrow samples 
Collection tube 
description and/or 
additive (color of 
tube top) 
Component 
Available 
Cell Surface 
Markers 
(Flow 
Cytometry) 
DNA 
Banking 
EDTA (purple) 
Plasma 
 
 
X 
EDTA (purple) 
DNA 
 
X 
X 
Na Heparin (green) 
PBMCs 
X 
 
X 
No anticoagulant 
(red) 
serum 
 
 
X 
ACD (yellow) 
Plasma 
(marrow) 
 
 
X 
ACD (yellow) 
PBMCs 
(marrow) 
X 
 
X 
Note: All collection tubes need to be labeled with the protocol number, patient initials 
(last name, first name), study patient ID number (if available), specimen type (bone 
marrow or peripheral blood) and date of collection as well as the arm of the study (A or B 
or C). 
14.3 
Shipping and Handling 
14.31 Kits will be provided for non-Mayo Rochester sites for the samples collected in 
Section 14.1 . 
The kit contains supplies and instructions for collecting, processing, and shipping 
specimens. 
 
Participating institutions may obtain kits by e-mailing 
 
.  E-mail requests should include the site address, 
contact information and number of kits being requested. 
 
Kits will be sent via FedEx® Ground at no additional cost to the participating 
institutions.  Allow 3 to 4 business days to receive the kits. 
14.32 Label specimen tubes with the protocol number, patient initials (last name, first 
name), study patient ID number (if available), specimen type (bone marrow or 
peripheral blood) and date of collection, as well as the arm of the study (A or B 
or C) 
14.33 Collect all specimens according to instructions in Appendix V and table above. 




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Multiple surface and intracellular antigens will be analyzed using flow 
cytometric method. Apoptosis status of the leukemic cells will also be analyzed. 
CD38, ZAP-70 and CD49d status will be determined by flow cytometric method.  
14.45 Plasma from the enrolled patients will be stored for future study of multiplex 
cytokine, biomarker analysis and microvesicle analysis. 
14.46 RNA will also be isolated from CLL PBMC and stored for future use of analysis 
of gene expression profiling of the involved signal pathways. IGHV status will 
be assessed using RNA from CLL B-cells using previously described methods 
(Jelinek Br J Haematol.115 (4):854-61) 
14.47 Peripheral blood CLL FISH panel (CLL/SLL arm only): may be performed using 
a portion of the research samples if not performed clinically. 
14.5 
Residual specimens: A portion of the plasma, DNA, RNA, bone marrow aspirates and 
white blood cells will initially be analyzed as described in 14.41.  After the above 
correlative studies are completed and according to patient consent information (see 
Section 6.34), remaining blood products will be transferred to 
 
 and stored frozen by 
 laboratory until specific 
analyses are identified.  Future research that is in the area of the studies outlined above 
will not require resubmission to the IRB; however, if a new use of the tissue or blood is 
requested, then this request will be presented for IRB review and approval. 


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15.0 
Drug Information 
15.1 
Pembrolizumab (MK-3475, SCH 900475, Keytruda®) 
15.11 Background:  Pembrolizumab is a potent humanized IgG4 monoclonal antibody 
with high specificity of binding to the PD-1 receptor, thus inhibiting its 
interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
15.12 Formulation:  Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial. 
15.13 Preparation and storage: Vials should be stored in the refrigerator at 
temperatures between 2-8°C.   
Drug concentrate is further diluted with normal saline (or 5% dextrose in the 
concentration range of 1 to 10 mg/mL).  The infusion solution in the IV bag 
should be immediately administered. Diluted pembrolizumab solutions may be 
stored at room temperature for a cumulative period of up to 6 hours. This 
includes room temperature storage of admixture solutions in the IV bags and the 
duration of infusion. The product can also be stored under refrigeration at 2°C to 
8°C for no more than 96 hours from the time of dilution. If refrigerated, the 
diluted solution must be allowed to come to room temperature prior to 
administration. The solution must be discarded after 6 hours at room temperature 
or 96 hours under refrigeration 
15.14 Administration:  Pembrolizumab is administered by intravenous infusion over 
30 minutes via a 0.22 micron in-line filter. The final infusion volume must be 
between 1 and 10 mg/mL. Maximum rate of infusion should not exceed 6.7 
mL/minute through a peripheral or indwelling catheter. Flush the line with 0.9% 
NaCL following the completion of the infusion. 
15.15 Pharmacokinetic information: 
a)  Absorption – Because pembrolizumab is administered intravenously, it is 
immediately and completely bioavailable.  Steady -state concentrations of 
pembrolizumab are reached by 16 weeks of repeated dosing with a Q3W regimen 
and the systemic accumulation is 2.1-fold.  The peak concentration, trough 
concentration, and area under the plasma concentration versus time curve at 
steady state of pembrolizumab increased dose proportionally in the dose range of 
2 to 10 mg/kg Q3W.   
b)  Distribution – Pembrolizumab has a limited volume of distribution.  
c) Excretion –CL is approximately 23% lower after achieving maximal change at 
steady state compared with the first dose. The terminal elimination half-life (t ½) 
is estimated to be 22 days at steady state   
d)  Metabolism - Pembrolizumab is catabolized through non-specific pathways; 
metabolism does not contribute to its CL. 
15.16 Potential Drug Interactions:  There are no known significant drug interactions.   
15.17 Very common know potential toxicities, ≥ 10% 
Gastrointestinal disorders:  diarrhea, nausea, abdominal pain 
Skin and subcutaneous tissue disorders: rash, pruritis 
General disorders and administration site conditions: fatigue 
Common known potential toxicities, ≥1 to < 10%:   
Blood and lymphatic system disorders: anemia 


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Immune system disorders: infusion related reaction 
 
Endocrine disorders: hyperthyroidism, hypothyroidism 
Metabolism and nutrition disorders: decreased appetite 
Nervous system disorders: headache, dizziness, dysgeusia 
Respiratory, thoracic, and mediastinal disorders: pneumonitis, dyspnea, 
cough 
Gastrointestinal disorders: colitis, vomiting, constipation, dry mouth 
Skin and subcutaneous tissue disorders: severe skin reactions,  
vitiligo, dry skin, erythema 
Musculoskeletal and connective tissue disorders: arthralgia, myositis, 
musculoskeletal pain, , pain in extremity 
General disorders and administration site conditions: asthenia,  
edema, pyrexia, influenza like illness, chills 
Investigations: alanine aminotransferase increased, aspartate  
aminotransferase increased, blood alkaline phosphatase increased, blood 
creatinine increased 
 
 
Uncommon known potential toxicities, ≥0.1% to <1%: 
Infusion related reactions 
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, 
leukopenia, lymphopenia, eosinophilia 
Endocrine disorders: hypophysitis, adrenal insufficiency,  
Thyroiditis, hypopituitarism 
Metabolism and nutrition disorders: type I diabetes mellitus,  
hyponatremia, hypokalemia, hypocalcemia 
Psychiatric disorders: insomnia, confusional state 
 
 
 
Nervous system disorders: epilepsy, lethargy, peripheral  
Neuropathy 
Eye disorders: uveitis, dry eye 
Cardiac disorders: myocarditis, atrial fibrillation 
Vascular disorders: hypertension 
Gastrointestinal disorders: pancreatitis, dysphasia 
Hepatobiliary disorders: hepatitis 
Skin and subcutaneous tissue disorders: lichenoid keratosis, psoriasis, 
alopecia, dermatitis, dermatitis acneiform, eczema, hair color changes, 
papule 
Musculoskeletal and connective tissue disorders: tenosynovitis, myelitis 
Renal and urinary disorders: nephritis, acute kidney injury 
Investigations: blood bilirubin increased, amylase increased, 
hypercalcemia 
Respiratory: pneumonia aspiration 
 
Rare known potential toxicities, <0.1% (Limited to important or life-
threatening): 
Blood and lymphatic system disorders: immune thrombocytopenic 
purpura, hemolytic anemia 
Immune system disorders: sarcoidosis 
Nervous system disorders: Guillain-Barre syndrome, myasthenic syndrome, 
exacerbation of myasthenia gravis 
Gastrointestinal disorders: small intestinal perforation 


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Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, 
Stevens-Johnson syndrome, erythema nodosum 
The risk profile for pembrolizumab also includes two important potential risks: a) 
myasthenic syndrome, and b) an increased risk of severe complications (such as 
early severe graft versus host disease and venoocclusive disease) of allogeneic 
transplant in patients with hematologic malignancies who have previously been 
treated with PD-1 inhibitors.  
 
Patients with multiple myeloma who were treated with pembrolizumab in 
combination with either pomalidomide or lenalidomide and dexamethasone, had 
an increased number of serious side effects and deaths as compared to patients 
who received only dexamethasone and either pomalidomide or lenalidomide. The 
benefit-risk profile is unfavorable for the combination of pembrolizumab, 
pomalidomide, and dexamethasone in relapsed refractory multiple myeloma, and 
the combination of pembrolizumab, lenalidomide, and dexamethasone in newly 
diagnosed treatment-naive multiple myeloma. 
 
Post marketing reports identified Vogt-Koyanagi-Harada syndrome and 
hemophagocytic lymphohistiocytosis. 
 
15.18 Drug procurement:  Pembrolizumab will be provided free of charge to study 
participants by Merck. 
15.19 Nursing Guidelines:  
15.191 Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team immediately. 
Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt 
intervention of corticosteroids. 
15.192 Diarrhea can be seen however it is less common than that seen with anti-
CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to the 
study team immediately.  
15.193 Rash/pruritus/dermatitis is seen. Patients should report any rash to the 
study team. Treat per section 9.0 and monitor for effectiveness.  
15.194 Monitor LFT’s closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team immediately. 
15.195 Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, cough, 
chest pain, etc. to the study team immediately. Patients reporting these 
symptoms should have a pulse ox checked and consider immediate 
imaging per the treating MD. 
15.196 Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of fatigue and “not 


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feeling well”. Additional symptoms may be that of nausea, sweating and 
decreased activity tolerance. Instruct patients to report these signs or 
symptoms immediately and obtain appropriate labs as ordered by MD.  
15.197 Patients who are started on steroid therapy for any side effects of 
pembrolizumab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and be 
severe. Patients may be on steroid therapy for weeks. Instruct patients to 
report any increase or change in side effects with any dosage decrease as 
patients may need a slower taper.  
15.198 Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
15.199a Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines 
15.199b Patients who have undergone an allogenic bone marrow transplant, have 
an increased risk of severe complications including early GVHD, and 
venoocclusive disease, if they have previously been treated with 
pembrolizumab 
15.199c Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain , SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
15.199d Autoimmune hematologic disorders including ITP and hemolytic anemia 
have been reported.  Monitor blood counts closely and report any 
abnormalities to the study team. 
15.199e Rare neurologic disorders including Guillian-Barre syndrome and 
myasthenia gravis have been reported.  Instruct patients to report any 
neurologic symptoms including weakness, parasthesias or numbness, 
tingling to the study team immediately. 
15.2 
Idelalisib for Oral Administration (Zydelig®) 
15.21 Background: Idelalisib inhibits PI3Kδ kinase, which is highly expressed in 
malignant lymphoid B-cells and is central to multiple signaling pathways that 
drive proliferation. Through inhibition CXCR4 and CXCR5 signaling, Idelalisib 
inhibits homing and retention of malignant B-cells in the tumor 
microenvironment including lymphoid tissues and the bone marrow. 
15.22 Formulation: Idelalisib is available as 100 mg or 150 mg tablets. The 150 mg 
tablet is oval shaped, pink, and debossed with “150” on one side and “GSI” on 
the other side. The 100 mg tablet is oval-shaped, orange, and debossed with 
“100” on one side and “GSI” on the other side. 
Inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate and a tablet 
coating. The tablet coating consists of polyethylene glycol, talc, polyvinyl 
alcohol, and titanium dioxide and of FD&C Yellow #6/Sunset Yellow FCF 
Aluminum Lake (for the 100 mg tablet) and red iron oxide (for the 150 mg 
tablet). 
 
15.23 Preparation and storage: Dispense only in original container. Store between 


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20–30°C (68–86°F) with excursions permitted 15–30ºC  
(59–86ºF).   
15.24 Administration:  Refer to the treatment section for specific administration 
instructions. Idelalisib may be taken with or without food. Idelalisib should be 
swallowed whole. If a dose is missed by less than 6 hours, take the missed dose 
right away and take the next dose as usual. If a dose of Idelalisib is missed by 
more than 6 hours, advise the patient to wait and take the next dose at the usual 
time. 
15.25 Pharmacokinetic information: 
Absorption: Time to peak concentration in a fasting state is approximately 1.5 
hours. Administration with a high fat meal increased the AUC 1.4-fold. Idelalisib 
exposure increases in a less than dose-proportional manner. 
Distribution: 23 L at steady state 
Protein binding: > 84% 
Metabolism: Idelalisib is hepatically metabolized to its major metabolite, GS-
563117, via aldehyde oxidase and CYP3A. GS-563117 is inactive against PI3Kδ. 
Idelalisib undergoes minor metabolism by UGT1A4. 
Half-life elimination: Approximately 8 hours 
Time to peak: 1.5 hours 
Excretion: Feces (78%; 44% as GS-563117); urine (14%; 49% as GS-563117) 
15.26 Potential Drug Interactions:   
Idelalisib is metabolized primarily by CYP3A4. The AUC of Idelalisib was 
reduced by 75% when coadministered with a strong CYP3A inducer. Avoid 
coadministration with strong CYP3A inducers, such as rifampin, phenytoin, St. 
John’s wort or carbamazepine. 
 
The AUC of Idelalisib was increased 1.8-fold when coadministered with a strong 
CYP3A inhibitor. If patients are taking concomitant strong CYP3A inhibitors, 
monitor for signs of Idelalisib toxicity. Follow dose modifications in the package 
insert for adverse reactions. 
  
Idelalisib is a strong CYP3A4 inhibitor. The AUC of sensitive CYP3A4 
substrates was increased 5.4 fold when Idelalisib was coadministered with a 
sensitive CYP3A4 substrate. Avoid coadministration of Idelalisib with CYP3A4 
substrates.  
 
Idelalisib also inhibits CYP2C8, CYP2C19, and UGT1A1. GS-563117 inhibits 
CYP2C8, CYP2C9, CYP2C19, CYP3A, and UGT1A1 in vitro. Idelalisib and 
GS-563117 are not likely to inhibit CYP1A1, CYP2B6, and CYP2D6. 
 
Idelalisib also induces CYP2B6, but does not induce CYP1A2 in vitro. GS-
563117 does not induce these enzymes. 
 
Idelalisib and GS-563117 are substrates of P-glcyoprotein (P-gp) and BCRP in 
vitro. Idelalisib is not a substrate of OATP1B1, OATP1B3, PAT1, OAT3, or 
OCT2. GS-563117 is not a substrate of OATP1B1 or OATP13. 
 
Idelalisib inhibits P-gp, OATP1B2, and OATP1B3, and GS-563117 inhibits 
OATP1B1, OATP1B3 in vitro. Idelalisib is not likely to inhibit BCRP, OCT2, 


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OAT1, or OAT3, and GS-563117 is not likely to inhibit P-gp, BCRP, OCT2, 
OAT1, or OAT3.


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15.27 Known potential toxicities:  
Warning: Fatal and serious toxicities: Hepatic, severe diarrhea/colitis, 
pneumonitis, and intestinal perforation. See full prescribing information for 
complete boxed warning. 
 
Hepatotoxicity: ALT/AST elevations >5 times ULN have occurred, and were 
generally observed during the first 12 weeks of therapy; transaminase elevations 
were reversible upon therapy interruption. Hepatotoxicity may recur upon 
rechallenge, even at a reduced dose; discontinue for recurrent hepatotoxicity. 
Avoid concomitant use with other hepatotoxic agents.  
 
Severe diarrhea/colitis: Fatal and/or serious and severe diarrhea or colitis 
occurred in 14% of Idelalisib-treated patients. Monitor for the development of 
severe diarrhea or colitis. Grade 3 or higher diarrhea or colitis has been reported 
in clinical trials. Diarrhea may occur at any time during therapy and responds 
poorly to antidiarrheal (antimotility) medications. The median time to resolution 
of diarrhea was 1 week to 1 month (following therapy interruption); 
corticosteroids were used in some cases to manage toxicity. Avoid concomitant 
use with other promotility agents. 
 
Pneumonitis: Fatal and serious pneumonitis can occur in Idelalisib-treated 
patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. 
Symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates, or an oxygen 
saturation decrease of more than 5% should be promptly evaluated. 
 
Intestinal perforation: Fatal and serious intestinal perforation can occur in 
Idelalisib-treated patients across clinical trials. In some patients, perforation was 
preceded by moderate to severe diarrhea. Monitor closely for new or worsening 
abdominal pain, chills, fever, nausea, or vomiting. Discontinue Idelalisib for 
intestinal perforation. 
 
Very common toxicities (≥10%):  
Central nervous system: Fatigue, insomnia, headache 
Dermatologic: Skin rash (, night sweats 
Gastrointestinal: Diarrhea, nausea, abdominal pain, decreased appetite, vomiting 
Hematologic: Neutropenia, anemia, thrombocytopenia 
Hepatic: increased AST/ALT, severe hepatotoxicity 
Neuromuscular/skeletal: Weakness 
Respiratory: Cough, pneumonia, dyspnea, upper respiratory tract infection 
Miscellaneous: Fever  
 
Common toxicities (≥ 1% and < 10%):  Peripheral edema 
 
Other toxicities: Anaphylaxis, hypersensitivity reaction, intestinal perforation, 
toxic epidermal necrolysis, severe and/or life threatening (grade 3 or higher) 
cutaneous reactions such as exfoliative dermatitis, rash (generalized, 
erythematous, macular-papular, pruritic, exfoliative) 
 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler.


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15.29 Nursing Guidelines 
15.291 Idelalisib can be taken with or without food and should be taken twice 
daily. Tablets must be swallowed whole. Doses should only be made up 
if less than 6 hours.  
15.292 Gastrointestinal side effects are common, including diarrhea (including 
severe colitis), nausea, vomiting, etc.  Treat symptomatically and 
monitor for effectiveness. Note that the diarrhea caused by this agent 
tends to respond poorly to antidiarrheal agents.  Patients may need 
corticosteroids. 
15.293 Serious and/or fatal hepatotoxicity can be seen. Monitor LFT’s and 
instruct patients to report any abdominal pain, or jaundice to the study 
team.  
15.294 Monitor CBC w/diff as neutropenia and thrombocytopenia is common. 
Instruct patients to report any signs or symptoms of infection and/or any 
unusual bruising or bleeding to the study team. 
15.295 Rarely patients may experience pneumonitis. Instruct patients to report 
cough, shortness of breath, dyspnea, or chest pain to the study team. 
15.296 Patients may experience pyrexia and/or chills. Rule out infection and 
treat symptomatically.  Monitor for effectiveness. 
15.297 Warn patients of potential fetal harm. Instruct women of child bearing 
potential to use appropriate and effective birth control while on agent.  
15.3 
Ibrutinib for Oral Administration (Imbruvica®) 
15.31 Background: Ibrutinib is a potent and irreversible inhibitor of Bruton’s tyrosine 
kinase (BTK), an integral component of the B-cell receptor (BCR) and cytokine 
receptor pathways. Constitutive activation of B-cell receptor signaling is 
important for survival of malignant B-cells; BTK inhibition results in decreased 
malignant B-cell proliferation and survival. 
15.32 Formulation: Commercially available for oral administration as a capsule: 70 
mg, 140mg (limited availability). Commercially available for oral administration 
as a tablet: 140 mg, 280 mg, 420 mg, and 560 mg.. 
15.33 Preparation and storage: Refer to package insert for complete dispensing 
instructions. Store capsules and tablets at room temperature between 20°C and 
25°C (68°F and 77°F). Excursions are permitted between 15° and 30°C (59°F to 
86°F).   Keep in original container.. 
15.34 Administration:  Refer to the treatment section for specific administration 
instructions.  The manufacturer recommends Ibrutinib should be taken with water 
at the same time every day. Swallow capsules whole. Do not open, break, or 
chew the capsules. Do not cut, crush, or chew the tablets. Maintain adequate 
hydration during treatment. Hazardous agent; use appropriate precautions for 
handling and disposal. 
15.35 Pharmacokinetic information: 
Distribution: ~10,000 L  
Bioavailability: Administration with food increased the maximum concentration 
by ~2 to 4-fold and the AUC 2-fold (compared with overnight fasting) 


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Protein binding: ~97%. Administration under fasting conditions resulted in 
exposure of ~60% compared to when administered either 30 minutes before or 
after a meal, or 2 hours after a high-fat meal.   
Metabolism: Hepatic via CYP3A (major) and CYP2D6 (minor) to active 
metabolite PCI-45227 
Half-life elimination: 4 to 6 hours 
Time to peak: 1 to 2 hours 
Excretion: Feces (80%; ~1% as unchanged drug); urine (<10%, as metabolites) 
15.36 Potential Drug Interactions:  
Metabolism Effects: Ibrutinib is primarily metabolized by cytochrome P450 
enzyme 3A4/5.  Avoid concomitant use of Ibrutinib with any of the following:  
CYP3A4 inducers (strong), CYP3A4 inhibitors (strong or moderate) and herbs 
that are CYP3A4 inducers or inhibitors.  The levels of Ibrutinib may be increased 
by CYP3A4 inhibitors and decreased by CYP3A4 inducers (the active metabolite 
has inhibitory activity towards Bruton’s tyrosine kinase that is approximately 15 
times lower than that of Ibrutinib). 
 
Transport Effects:  Ibrutinib is a P-glycoprotein/ABCB1 inhibitor and may 
increase the serum concentrations of:  afatinib, bosutinib, brentuximab, 
colchicine, active metabolites of dabigatran etexilate, doxorubicin, edoxaban, 
everolimus, ledipasvir, naloxegol, pazopanib, prucalopride, rifaximin, 
rivaroxaban, silodosin, topotecan and vincristine. 
 
Ibrutinib may enhance the adverse/toxic effect of clozapine, leflunomide, 
natalizumab, pimecrolimus, tofacitinib, tacrolimus, and live vaccines.  It may 
also enhance the adverse/toxic effect of anticoagulants and agents with 
antiplatelet properties.  Dipyrone may enhance the adverse/toxic effect of 
Ibrutinib. 
 
Grapefruit juice and Seville oranges moderately inhibit 3A4 and may increase 
Ibrutinib exposure. 
15.37 Known potential toxicities: Consult the package insert for the most current and 
complete information.  
Common known potential toxicities, >10%: 
Cardiovascular: Peripheral edema, hypertension 
Central nervous system: Fatigue, dizziness, headache, anxiety, chills 
Dermatologic: Skin rash, skin infection, pruritis 
Endocrine & metabolic: Increased uric acid, Hyperuricemia, hypoalbuminemia; 
hypokalemia, dehydration 
Gastrointestinal: Diarrhea, nausea, constipation, abdominal pain, vomiting, 
decreased appetite, stomatitis, dyspepsia, gastroesophageal reflux disease, upper 
abdominal pain 
Genitourinary: Urinary tract infection 
Hematologic & oncologic: Decreased platelet count, bruise, neutropenia, 
decreased hemoglobin, hemorrhage, petechial, malignant neoplasm (secondary) 
Infection:  infection 
Neuromuscular & skeletal: Musculoskeletal pain, arthralgia, muscle spasm, 
weakness, arthropathy 
Ophthalmic:  Dry eye syndrome, increased lacrimation, blurred vision, decreased 
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Respiratory:  Upper respiratory tract infection, dyspnea, sinusitis, cough, 
oropharyngeal pain, pneumonia, epistaxis, bronchitis 
Miscellaneous: Fever, , falling 
 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Atrial fibrillation, atrial flutter 
Infection: Sepsis 
 
Limited to important or life threatening: 
Renal: Renal failure Increased serum creatinine 
 
Limited to important or life threatening:  Abnormal platelet aggregation, 
hepatic failure, hypersensitivity (includes anaphylactic shock, angioedema, 
urticaria), interstitial pulmonary disease, onychoclasis, pneumonia due to 
Pneumocystis carinii, pneumonitis, progressive multifocal leukoencephalopathy, 
reactivation of HBV, renal failure, Stevens-Johnson syndrome, tumor lysis 
syndrome 
 
15.38 Drug procurement:  Commercial supplies.  Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
15.39 Nursing Guidelines  
15.391 There are numerous drug to drug interactions. Record all of patient’s 
medications including OTC, and herbal use. Avoid concomitant use with 
agents as listed in section 15.16. 
15.392 Patients should be instructed to avoid eating grapefruit (including juice) 
and Seville oranges while on Ibrutinib. 
15.393 Peripheral edema is common. Instruct patients to report this to the study 
team. 
15.394 Gastrointestinal side effects are common (diarrhea, nausea, constipation, 
abdominal pain, vomiting, etc). Treat symptomatically and monitor for 
effectiveness of intervention. 
15.395 Monitor CBC w/diff. Instruct patients in energy conserving lifestyle 
(anemia) and to report any unusual bruising or bleeding and/or signs or 
symptoms of infection to study team. 
15.396 Arthralgias, Myalgias, and muscle spasm can be seen. Treat 
symptomatically and monitor for effectiveness. 
15.397 Monitor renal function/uric acid levels, especially in patients who may 
be experiencing dehydration. 
15.398 Respiratory symptoms may include, cough, SOB, and URI. Instruct 
patients to report these symptoms to the study team. 
15.399a Rarely patients can experience secondary skin cancers. Instruct patients 
to report any new skin lesions to the study team. 
15.399b Rash can be seen. Instruct patient to report to study team. 
15.399c Cardiac arrhythmias have been seen with this agent including a-fib, atrial 
flutter and ventricular tachyarrhythmia’s, some of which have led to 


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death.  Instruct patients who experience any palpitations, 
lightheadedness, syncope, or SOB to seek medical care immediately.  
This is especially important in patients who have pre-existing cardiac 
issues.  


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16.0 
Statistical Considerations and Methodology  
16.1 
Overview:  This Phase II study will utilize a one-stage binomial design in each arm 
independently (Arms A, B, and C) to assess the overall response rate associated with 
single-agent MK-3475 in patients with relapsed and progressive CLL/SLL, including 
CLL patients with Richter’s transformation (RS) or Hodgkin’s transformation (Arm A 
and Arm C) and other types of relapsed and progressive low grade B cell NHL including 
FL, WM and marginal zone lymphoma (Arm B). 
16.11 Endpoint:  The primary endpoint of this trial is the proportion of patients who 
achieve a confirmed response to single-agent MK-3475.  A confirmed response is 
defined to be a PR, nPR, CCR, CRi or CR (Arms A and B) or CMR, PMR, PR, 
or CR (Arm C) noted as the objective status at any time while on single-agent 
MK-3475.  All patients meeting the eligibility criteria who have signed a consent 
form and have begun treatment will be evaluable for response, with the exception 
of patients determined to be a major violation. 
16.12 Sample Size:  This study is expected to require a maximum of 23 evaluable 
patients each in Arm A and Arm B. We anticipate accruing 1 additional patient in 
each arm to account for ineligibility, cancellation, major treatment violation, or 
other reasons. Therefore, this study is expected to accrue between 46 - 48 
patients in these two arms. 
As of MCCC Addendum 3, due to promising response observed in CLL patients 
with Richter’s transformation, an additional arm (Arm C) with 17 evaluable 
patients is added to the trial.  We anticipate accruing 3 additional patients to 
account for ineligibility, cancellation, major treatment violation, or other reasons 
for a total of 20 patients on Arm C. These patients will be accrued to allow better 
evaluation of response and toxicity of single agent MK 3475 in patients with 
Richter’s transformation.  This study is now expected to accrue a maximum of 68 
patients. 
16.13 Accrual Rate and Study Duration:  The anticipated accrual rate is approximately 
2-4 patients per month. Therefore, the accrual period for this phase II study is 
expected to be approximately 2-3.0 years. The final analysis can begin as soon as 
the last patient has been observed for 6 months, or at approximately 3.0-3.5 
years. 
MCCC Addendum 3: In approximately 20 months, the study has accrued 41 
patients. Based on current accrual rates, the total accrual period is now expected 
to be approximately 3.0 years.  The final analysis can begin as soon as the last 
patient has been observed for 6 months, or approximately 3.5 years from trial 
opening. 
16.2 
Statistical Design: 
16.21 Decision Rule for Arms A and B (to be evaluated in each arm independently):   
MK-3475 monotherapy induces an ORR of 39% in patients with ipilimumab-
naive melanoma by central independent RECIST review. The potential activity 
of this agent in relapsed CLL or low grade NHL has not been tested. Previous 
approved monoclonal antibodies, alemtuzumab or rituximab, have achieved ~20-
30% ORR in CLL. We expect that CLL patients who develop resistance to novel 
CLL therapies will enroll into this clinical study. It is completely unknown how 
CLL patients will respond to any types of CLL therapy after they developed 


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Ibrutinib resistance. Therefore, it is logical to hypothesize that 30% ORR will be 
worthy of further testing in relapsed CLL and low grade NHL patients.  
 
The largest success proportion where the proposed treatment strategy would be 
considered ineffective in this population is 10%.  The smallest success proportion 
that would warrant subsequent studies with the proposed treatment strategy in 
this patient population is 30%.  The following one-stage binomial design uses 23 
evaluable patients to test the null hypothesis that the true success proportion in a 
given patient population is at most 10%. 
16.211 Final Decision Rule:  Enter 23 evaluable patients into the study. If 4 or 
fewer successes are observed in the first 23 evaluable patients, we will 
consider this regimen ineffective in this patient population. If 5 or more 
successes are observed in the first 23 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
population. 
16.212 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.34. 
16.22 Assuming that the number of responses is binomially distributed, with a 
significance level of 7%, the probability of declaring that the regimen 
warrants further studies (i.e., statistical power) under various response 
proportions can be tabulated as a function of the true response proportion 
as shown in the table below. 
 
If the true success proportion is… 
0.10 
0.15 
0.20 
0.25 
0.30 
Then the probability of declaring that 
the regimen is promising and warrants 
further study is… 
0.07 
0.26 
0.50 
0.72 
0.86 
 
16.23 Decision Rule for Arm C: 
In the 9 Richter’s transformation patients accrued to Arm A of this study, 4 
patients were classified as a PET-CT or CT response by the Lugano 2014 
response criteria.   Due to the promising efficacy in selected patients with 
Richter’s transformation, Arm C is being added to further test efficacy of this 
agent in this patient population.  A confirmed response rate of 40% would be 
considered promising and would be of significant clinical interest. However, a 
response rate of 15% would be considered ineffective. 
 
The largest success proportion where the proposed treatment strategy would be 
considered ineffective in this population is 15%.  The smallest success proportion 
that would warrant subsequent studies with the proposed treatment strategy in 
this patient population is 40%.  The following one-stage binomial design uses 17 
evaluable patients to test the null hypothesis that the true success proportion in a 
given patient population is at most 15%. 
16.231 Final Decision Rule:  Enter 17 evaluable patients into the study. If 4 or 
fewer successes are observed in the first 17 evaluable patients, we will 
consider this regimen ineffective in this patient population. If 5 or more 


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successes are observed in the first 17 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
population. 
16.232 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.34. 
16.24 Assuming that the number of responses is binomially distributed, with a 
significance level of 10%, the probability of declaring that the regimen warrants 
further studies (i.e., statistical power) under various response proportions can be 
tabulated as a function of the true response proportion as shown in the table 
below. 
 
If the true success proportion is… 
0.15 
0.20 
0.25 
0.30 
0.35 
0.40 
Then the probability of declaring that 
the regimen is promising and warrants 
further study is… 
0.10 
0.24 
0.43 
0.61 
0.77 
0.87 
 
16.25 Other considerations: Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study 
16.3 
Analysis Plan (to be evaluated in each arm independently) 
16.31 Primary Outcome Analyses: 
16.311 Definition: The primary endpoint of this trial is the proportion of patients 
who achieve a confirmed response to single-agent MK-3475.  A 
confirmed response is defined to be a PR, nPR, CCR, CRi or CR (Arms 
A and B) or PMR, CMR, PR or CR (Arm C) noted as the objective status 
at any time while on single-agent MK-3475.  All patients meeting the 
eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for response, with the exception of patients 
determined to be a major violation.  For CLL patients with Richter’s 
transformation, confirmed response is determined by response criteria 
defined for Richter’s transformation. 
16.312 Estimation:  In each arm, the proportion of successes will be estimated 
by the number of successes divided by the total number of evaluable 
patients in that arm. Exact binomial confidence intervals for the true 
success proportion will be calculated.  In addition, the confirmed 
response rate for all Richter’s transformation patients (9 patients from 
Arm A and all patients in Arm C) will be calculated. 
16.32 Secondary Outcome Analyses (to be evaluated in each arm independently;  Arm 
C analyses may include the 9 Richter’s transformation patients from Arm A):  
(For all outcomes associated with combination therapy in Arms A and C, disease 
measurements obtained after the last cycle of single-agent therapy are set as the 
baseline measurements for combination therapy). 
16.321 Progression-free survival (PFS) for single-agent MK-3475 is defined as 


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the time from registration to the earliest date of documentation of disease 
progression while on single-agent MK-3475 or death due to any cause. In 
Arm A and Arm C, patients who initiate combination therapy for stable 
disease after 3 months of single-agent MK-3475 will be censored on the 
date that combination therapy is initiated. 
In Arm A and Arm C, PFS for the combination of MK-3475 and the 
signal inhibitor is defined as the time from intiation of treatment with the 
combination therapy to the earliest date of documentation of disease 
progression while on combination therapy or death due to any cause.  
 
The distribution of progression-free survival will be estimated using the 
method of Kaplan-Meier. 
16.322 Treatment-free survial (TFS) for single-agent MK-3475 is defined as the 
time from registration to the date of initiation of subsequent treatment for 
CLL/SLL or lymphoma or death due to any cause.  In Arm A and Arm 
C, the initiation of combination therapy with MK-3475 and the signal 
inhibitor will be considered subsequent treatment. 
In Arm A and Arm C, TFS for the combination of MK-3475 and the 
signal inhibitor is defined as the time from initiation of combination 
therapy to the date of initiation of subsequent treatment for CLL/SLL or 
death due to any cause. 
 
The distribution of treatment-free survival will be estimated using the 
method of Kaplan-Meier. 
16.323 The time to next treatment (TNT) for single-agent MK-3475 is defined 
as the time from registration to the date of initiation of subsequent 
treatment for CLL/SLL or lymphoma. In Arm A and Arm C, the 
initiation of combination therapy with MK-3475 and the signal inhibitor 
will be considered subsequent treatment. 
In Arm A and Arm C, TNT for the combination of MK-3475 and the 
signal inhibitor is defined as the time from initiation of combination 
therapy to the date of initiation of subsequent treatment for CLL/SLL.  
 
The distribution of time to next treatment will be estimated using the 
method of Kaplan-Meier. 
16.324 The complete response rate will be estimated by the number of patients 
who achieve a CRi or CR (Arms A and B) or CMR or CR (Arm C) 
divided by the total number of evaluable patients. Complete response 
rate will be evaluated for single-agent MK-3475 in each arm and also for 
the combination of MK-3475 and the signal inhibitor in Arm A and C.  
All evaluable patients will be used for this analysis. Exact binomial 95% 
confidence intervals for the true complete response rate will be 
calculated in each arm. 
16.325  Duration of response (DR) is defined for all evaluable patients who have 
achieved a PR, nPR, CCR, CRi, or CR (Arms A and B) or PMR, CMR,  
PR or CR (Arm C) as the date at which the patient’s objective status is 
first noted to be a PR, nPR, CCR, CRi, or CR (Arms A and B) or PMR, 
CMR, PR or CR (Arm C) to the earliest date relapse is documented. 
Duration of response will evaluated for single-agent MK-3475 in each 


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arm and also for the combination of MK-3475 and the signal inhibitor in 
Arm A and C. The distribution of duration of  response will be estimated 
using the method of Kaplan-Meier. 
16.326 Overall survival is defined as the time from registration to death due to 
any cause. The distribution of overall survival will be estimated using the 
method of Kaplan-Meier. 
16.327 Arm A and Arm C: The overall response rate for the combination of 
MK-3475 and the signal inhibitor (targeted agents) will be estimated by 
the number of patients with an objective status of CR, CRi, nPR, CCR or 
PR (Arm A) or PMR, CMR, PR or CR (Arm C) while on the 
combination therapy divided by the total number of evaluable patients. 
All evaluable patients who receive the combination therapy will be used 
for this analysis. Exact binomial 95% confidence intervals for the true 
overall response rate to the combination will be calculated.  In addition, 
the responders on this study will be further examined in an exploratory 
manner to determine if there are any patterns in prognostic factors or 
disease characteristics, including whether the patient had a Richter’s 
transformation or Ibrutinib-resistant disease, for both single-agent MK-
3475 and combination therapy responders. 
16.328 Adverse Events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s).  The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns.  
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration.  Adverse events will be 
evaluated for single-agent MK-3475 in each arm and also for the 
combination of MK-3475 and the signal inhibitor in Arm A and Arm C. 
16.33  Correlative Analyses: 
16.331 PD-1, PD-L1 and PD-L2 will be measured for each patient at baseline 
and during treatment.  Each measure will be summarized descriptively 
by median, min, max and interquartile range.  Overall response and 
complete response will be correlated with each measure using Wilcoxon 
rank sum test.  The relationship between each measure and time to event 
measures (DR, TNT, PFS) will be evaluated using Cox proportional 
hazard models. 
16.332 Markers of immune modulation and immune profiles will be summarized 
descriptively by median, min, max, and interquartile range (continuous 
factors) or frequency distribution (categorical factors) at each time point.   
Patterns over time will be summarized by absolute difference or relative 
change.  Changes across time will be assessed using paired analyses, 
including Wilcoxon signed rank tests for continuous measures and 
McNemar’s tests for categorical measures.  Overall response and 
complete response will be correlated with continuous factors using 
Wilcoxon rank sum tests.   Jitplots will be used to visually examine 
differences between groups for continuous factors.  Overall response and 
complete response will be correlated with categorical factors using 
Fisher’s exact tests. 


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16.34 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final endpoint 
estimates and confidence intervals. 
16.4 
Safety Analysis Phase (Arm A and B only): 
A safety analysis will be performed after the first 12 patients (6 each arm for Arm A and 
B) have been accrued to the study.   Accrual will be temporarily halted while these 
patients are followed for one cycle to assess adverse events.  If 2 or more of the first 6 
patients in either arm experience a DLT as defined below, then accrual will continue to 
be temporarily suspended to the arm affected.  All toxicity data will be reviewed by the 
study team and a decision will be made about whether the starting dose needs to be 
adjusted or the protocol should be continued.    
 
Toxicity will be measured per NCI-CTCAE version 4. DLT is defined as an adverse 
event possibly, probably, or definitely related to study treatment that meets one of the 
following: 
• 
hepatic toxicity defined as AST or ALT > 5 - 10X ULN for > 4 weeks;    Total 
bilirubin > 5X ULN for > 4 weeks ;  Concurrent AST or ALT > 3X ULN and 
total bilirubin > 2X ULN (excluding liver involvement by  CLL or lymphoma)  
for > 4 weeks (potential Hy’s Law case) 
• 
grade 4 non-hematological toxicity[except weight loss or  fatigue or laboratory 
abnormalities  not associated with clinical sequelae] lasting longer than 4 weeks 
despite of holding therapy and supportive treatments 
• 
Any grade 5 AE  
16.5 
Data & Safety Monitoring: 
16.51 The principle investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
16.52 Adverse Event Stopping Rules (to be evaluted in each arm independently for 
single-agent MK-3475 and separately for combination therapy): The stopping 
rules specified below are based on the knowledge available at study 
development.  We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation.  The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
Single-agent MK-3475: Accrual will be temporarily suspended to the affected 
arm if at any time we observe events considered at least possibly related to study 
treatment during cycles with single-agent MK-3475 (i.e. an adverse event with 
attribute specified as  “possible,” “probable,” or “definite”) that satisfy one of the 
following: 
• 
If 4 out of the first 12 treated patients experience a DLT as defined in Section 
16.4 


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• 
If after the first 12 patients have been treated, 30% of all patients experience 
a DLT as defined in Section 16.4. 
 
Combination of MK-3475 and signal inhibitor (Ibrutinib or Idelalisib) in Arm A 
and Arm C:  Initiation of treatment with the combination (addition of Ibrutinib or 
Idelalisib) will be halted in Arm A and Arm C if at any time we observe events 
considered at least possibly related to study treatment during cycles with the 
combination (i.e. an adverse event with attribute specified as “possible,” 
“probable,” or “definite”) that satisfy one of the following: 
 
• 
If 2 out of the first 6 treated patients experience a DLT as defined in Section 
16.4 
• 
If after the first 6 patients have been treated, 30% of all patients experience a 
DLT as defined in Section 16.4. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
16.6 
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
along with other required information for this study will be reported on 
ClinicalTrials.gov. For purposes of timing of the Results Reporting, the initial estimated 
completion date for the Primary Endpoint of this study is 3.5 years after the study opens 
to accrual. The definition of “Primary Endpoint Completion Date” (PECD) for this study 
is at the time all patients registered have achieved a response or have discontinued 
treatment before achieving a response. 
16.7 
Inclusion of Women and Minorities 
16.71 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.72 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses.


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16.73 The geographical region served by MCCC has a population which includes 
approximately 3% minorities.  Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 30% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
Accrual Estimates by Gender/Ethnicity/Race  
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
2 
0 
2 
Not Hispanic or Latino 
20 
46 
0 
66 
Ethnic Category: Total of all subjects* 
20 
48 
0 
68 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
0 
2 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
20 
46 
0 
66 
Racial Category: Total of all subjects* 
20 
48 
0 
68 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial groups 
of Africa.  Terms such as “Haitian” or “Negro” can be used in addition to “Black or 
African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 


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17.0 
Pathology Considerations/Tissue Biospecimens:  
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
Pathology 
Review/ 
Correlative 
Study  
Mandatory 
or Optional 
Type of 
Tissue/ 
Slides to 
Collect 
Block, Slides, Core, 
etc. (# of each to 
submit) 
Visit 1: 
Baseline  
Visit 2: 
At 
Progressi
on 
Specific 
details for the 
submission 
Pathology 
review: 
Confirm 
diagnosis  
Mandatory 
for non-
mayo sites 
H & E, 
stained 
slides 
 All H&E stained 
diagnostic slides,  
X 
 
17.2 
Correlative 
Study:  
Mandatory 
Paraffin 
Tissue block 
(preferred) or  
unstained slides (18 
slides),  4-5 microns 
each 
 
X 
X 
17.3 
 
17.2 
Diagnostic Slides from Original and /or Recurrent Tissue to confirm diagnosis 
Central pathology review is not required as long as the tissue diagnosis of lymphoma was 
confirmed by a Mayo pathologist or other academic centers. If the tissue diagnosis is not 
confirmed by a Mayo pathologist/other academic centers, the slides will need to be 
reviewed to confirm the diagnosis. Completion of central pathology review is not 
required prior to registration; however materials for central review must be reviewed 
within 42 days after registration. 
17.21 Central pathology review will be conducted as needed for confirmation of 
diagnosis by
 and colleagues at Mayo Clinic Rochester if 
the initial tissue biopsy was not performed and evaluated at Mayo Clinic/other 
academic centers.   
Required materials: 
• 
Lymphoma Pathology Reporting Form (Complete Section I only) 
• 
Tissue Submission Form 
• 
Bone marrow biopsy report  
• 
Tumor tissue pathology report 
• 
Paraffin block containing tumor tissue from the most recent tumor tissue biopsy 
is preferred, not bone marrow or peripheral blood.  If the institution is unwilling 
to release a block, 18 unstained, charged slides cut at 4µ should be submitted.  
Slides should be placed in appropriate slide container. 
• 
All tumor tissue diagnostic H&E stained slides 
• 
Tumor tissue immunochemistry or immunophenotyping by flow cytometry report 
(if available) 
• 
FISH report if available 
 




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17.4 
Background and Methodology 
17.41 Background: accumulating evidence showed that the clinical response of 
checkpoint inhibitor is likely associated with tumor PD-L1 expression as well as 
tumor exomic mutation burden(Garon, Rizvi et al. 2015; Rizvi, Hellmann et al. 
2015).  Therefore, we plan to test the spectrum of tumor mutation using 
WES/targeted sequencing as well as tumor PD-L1 and other marker staining with 
immunohistochemistry analysis. 
17.42 Sequencing:  Genomic DNA will be extracted from formalin-fixed, paraffin-
embedded tissue blocks.  H&E-stained sections from each case will be reviewed 
by an expert hematopathologist and representative blocks with at least 30% 
tumor cells will be selected.  10 x 5-micron sections will be cut from blocks in 
the Mayo Clinic Pathology Research Core (based on tissue area of 25 
mm2).  DNA will be extracted in the Mayo Clinic Biospecimens Accessioning 
and Processing Core using the Qiagen FFPE DNA extraction kit.  DNA 
quantitation will be performed using a Qubit fluorometer prior to sequencing. 
17.43 Expression of PD-L1 has been demonstrated to associate with clinical response 
of cancer patients treated with pembrolizumab. It is also established that CD8+ 
cytotoxic T cell response is critical to mediate anti-tumor immunity. Therefore, 
multiple markers including T cell, tumor cells, as well as related co-stimulatory 
and inhibitory markers will be stained to identify if there is any association of 
expression of these markers with clinical response. The RNA expression of 
immune markers can also be assessed using nanostring method in collaboration 
with Merck biomarker research team. 


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18.0 
Records and Data Collection Procedures   
18.1   Submission Timetable 
Initial Material(s)  
 
 
CRF 
 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study  
≤2 weeks after registration 
Adverse Event  – Baseline  
Measurement  – Baseline 3 
Immunophenotyping Reports including 
CD38, CD49d, and ZAP-701, 2 (CLL 
patients only) 
IGHV Mutation Analysis Report1 (CLL 
patients only) 
Peripheral Smear Report1 (CLL patients 
only)  
CLL FISH Report1 (CLL patients only) 
Bone Marrow Biopsy Report1 
CT Scan Report1 
Pathology Report (NHL patients only) 
Pathology Reporting Lymphoma4 
Bone Marrow Biopsy – Baseline (CLL/SLL 
Patients Only) 
Research Blood Submission – Baseline  
Research Bone Marrow Aspirate 
Submission – Baseline  
Research Tissue Submission - Baseline 
FISH Results (CLL/SLL Patients Only) 
Other Laboratory Results 
End of Active Treatment/Cancel 
Notification  
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
1.  Submit copy of the report, Attention: 
. 
2.  For patients who previously had full flow immunophenotyping performed and at pre-study workup 
had limited repeat flow immunophenotyping, submit a copy of both reports. 
3.  See Section 11.0 to determine which response criteria will be utilized. 
4.  See Section 17.0 if central pathology review is required based on requirements in Section 4.1. 


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Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during 
treatment 
At end of treatment 
Observation 
Evaluation/Treatment  
X2 
X 
 
Evaluation/Treatment (Arms A 
and C – Continuation) 
X2 
X 
 
Evaluation/Observation  
 
 
X1 
Nadir/Adverse Event  
X 
X 
X 
Measurement  6 
X 
X 
X 
Bone Marrow Biopsy Report3 
X 
 
 
CT Scan Report3 
X4 
 
 
FISH Results (CLL/SLL Patients 
Only) 
 
X5 
X5 
Other Laboratory Results 
X4 
 
 
Bone Marrow Biopsy (CLL/SLL 
Patients Only) 
X4 
 
 
Research Blood Submission (see 
Section 14.0) 
X 
X5 
X5 
Research Bonne Marrow 
Aspirate Submission (see Section 
14.0) 
X 
 
 
End of Active Treatment/Cancel 
Notification  
 
X 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
1.  Complete at each evaluation during Observation (see Section 4.0). 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
3. Submit copy of the report, Attention: 
 
4. Complete when required per the test schedule. 
5. Complete at time of progression. 
6. See Section 11.0 to determine which response criteria will be utilized. 


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Follow-up Material(s)  
 
CRF 
Event Monitoring Phase1 
q. 6 months 
until PMD/PD 
or subsequent 
treatment 
At 
PMD/PD 
or 
subseque
nt 
treatment  
q. 12 
mos. 
after 
PMD/PD 
or 
subseque
nt 
treatment  
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring  
X2 
X2 
X 
X 
At each 
occurrence 
1. If a patient is still alive 4 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the MCCC Operations Office, Attention: 
. 
 


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19.0  
Budget 
19.1 
Costs charged to patient:  All routine clinical care. MK-3475 will be provided free of 
charge by Merck.  
19.2 
Tests to be research funded: Correlative studies outlined in Sections 14.0. 
19.3 
Other budget concerns: Protocol administration, study coordinator time, data 
management, and statistical analysis efforts will be funded by Merck. 


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20.0 
References 
Armand, P., A. Nagler, et al. (2013). "Disabling immune tolerance by programmed death-1 
blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for 
diffuse large B-cell lymphoma: results of an international phase II trial." Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 31(33): 
4199-4206. 
Brusa, D., S. Serra, et al. (2013). "The PD-1/PD-L1 axis contributes to T-cell dysfunction in 
chronic lymphocytic leukemia." Haematologica 98(6): 953-963. 
Byrd, J. C., R. R. Furman, et al. (2013). "Targeting BTK with Ibrutinib in relapsed chronic 
lymphocytic leukemia." The New England journal of medicine 369(1): 32-42. 
Cubas, R. A., J. C. Mudd, et al. (2013). "Inadequate T follicular cell help impairs B cell immunity 
during HIV infection." Nature medicine 19(4): 494-499. 
Fest, T., D. Rossille, et al. (2013). "Blood soluble PD-L1 protein in aggressive diffuse large B-
cell lymphoma impacts patient's overall survival." Blood 122(21). 
Fischer, K., P. Cramer, et al. (2011). "Bendamustine combined with rituximab in patients with 
relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of 
the German Chronic Lymphocytic Leukemia Study Group." Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 29(26): 3559-
3566. 
Francisco, L. M., P. T. Sage, et al. (2010). "The PD-1 pathway in tolerance and autoimmunity." 
Immunological reviews 236: 219-242. 
Galon, J., A. Costes, et al. (2006). "Type, density, and location of immune cells within human 
colorectal tumors predict clinical outcome." Science 313(5795): 1960-1964. 
Good-Jacobson, K. L., C. G. Szumilas, et al. (2010). "PD-1 regulates germinal center B cell 
survival and the formation and affinity of long-lived plasma cells." Nature immunology 
11(6): 535-542. 
Grote, D., s. Ziesmer, et al. (2013). "Interactions Between PD-1 and PD-L1 and PD-L2 Promote 
Malignant B-Cell Growth in Waldenstrom Macroglobulinemia." Blood 122(21). 
Hallek, M., B. D. Cheson, et al. (2008). "Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines." Blood 111(12): 5446-5456. 
Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic 
diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory 
Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 
1999;17:3835-3849. 
Hillen, F., C. I. Baeten, et al. (2008). "Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma." Cancer immunology, 
immunotherapy : CII 57(1): 97-106. 
Hiraoka, N. (2010). "Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology." International journal of clinical oncology 15(6): 544-551. 
Hochster, H., E. Weller, et al. (2009). "Maintenance rituximab after cyclophosphamide, 
vincristine, and prednisone prolongs progression-free survival in advanced indolent 
lymphoma: results of the randomized phase III ECOG1496 Study." Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 27(10): 1607-
1614. 
Kaplan, E. L., and Meier, P. (1958) Nonparametric Estimation from Incomplete Observations. 
Journal of the American Statistical Association 53, 457-481 
Kawamoto, S., T. H. Tran, et al. (2012). "The Inhibitory Receptor PD-1 Regulates IgA Selection 
and Bacterial Composition in the Gut." Science 336(6080): 485-489. 


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Kloor, M. (2009). "Lymphocyte infiltration and prognosis in colorectal cancer." The lancet 
oncology 10(9): 840-841. 
Muenst, S., S. Hoeller, et al. (2010). "Diagnostic and prognostic utility of PD-1 in B cell 
lymphomas." Disease markers 29(1): 47-53. 
Nunes, C., R. Wong, et al. (2012). "Expansion of a CD8(+)PD-1(+) replicative senescence 
phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and 
disease progression." Clinical cancer research : an official journal of the American 
Association for Cancer Research 18(3): 678-687. 
Ramsay, A. G., A. J. Clear, et al. (2012). "Multiple inhibitory ligands induce impaired T-cell 
immunologic synapse function in chronic lymphocytic leukemia that can be blocked with 
lenalidomide: establishing a reversible immune evasion mechanism in human cancer." 
Blood 120(7): 1412-1421. 
Rawstron, A. C., N. Villamor, et al. (2006). "International Standardized Approach for Flow 
Cytometric Residual Disease Monitoring in Chronic Lymphocytic Leukemia." Blood In 
Press. 
Riches, J. C., J. K. Davies, et al. (2013). "T cells from CLL patients exhibit features of T-cell 
exhaustion but retain capacity for cytokine production." Blood 121(9): 1612-1621. 
Rummel, M. J., N. Niederle, et al. (2013). "Bendamustine plus rituximab versus CHOP plus 
rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an 
open-label, multicentre, randomised, phase 3 non-inferiority trial." Lancet 381(9873): 
1203-1210. 
Smeltzer, J., J. jones, et al. (2013). "Changes in the tumor microenvironment associated with 
transformation in follicular lymphoma." Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology suppl. 
Talmadge, J. E., M. Donkor, et al. (2007). "Inflammatory cell infiltration of tumors: Jekyll or 
Hyde." Cancer metastasis reviews 26(3-4): 373-400. 
Westin, J., F. Chu, et al. (2012). "Phase II safety and efficacy study of CT-011, a humanized anti-
PD-1 monoclonal antibody, in combination with rituximab in patients with relapsed 
follicular lymphoma." Blood 120. 
Xerri, L., B. Chetaille, et al. (2008). "Programmed death 1 is a marker of angioimmunoblastic T-
cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia." 
Human pathology 39(7): 1050-1058. 
Yang, Z. Z., D. Grote, et al. (2013). "PD-1 Expression Defines Two Distinct T-Cell 
Subpopulations That Differentially Impact Patient Outcomes In Follicular Lymphoma " 
Blood 122(21). 
 
 


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Appendix I  NYHA Classification 
 
Class I:  
NO Symptoms with ordinary activity  
Class II:  
Symptoms with ordinary activity  
Class III:  
Symptoms with minimal activity 
Class IV:  
Symptoms at rest 


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Appendix II  Rai Classification 
0 
lymphocytosis (>5 x 109/L) 
I  
 
lymphocytosis and lymphadenopathy  
II  
 
lymphoctosis and splenomegaly +/- lymphadenopathy  
III 
 
anemia (Hgb < 11 g/dL) 
IV 
 
thrombocytopenia (platelets < 100 x 109/L) 


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Appendix III  ECOG Performance Status Scale 
 
 
ECOG Performance Status Scale 
 
Grade 
i) 
Descriptions 
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. 
 


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Appendix IV  Grading Scale for Hematologic Toxicity in CLL Studies1 
 
Decrease from 
Grade2 
Pretreatment value (%) 
Platelets3, 5 
Hemoglobin4, 5 
No change - 10% 
0 
0 
11-24% 
1 
1 
25-49% 
2 
2 
50-74% 
3 
3 
≥ 75% 
4 
4 
 
1. 
A decrease in circulating granulocytes is not being considered since it is not a 
reliable index in CLL. 
2. 
Grades:  1–mild; 2–moderate; 3–severe; 4–life–threatening.  Grade 5 (fatal) 
toxicity can potentially occur at any level of decrease from pretreatment values and will 
be recorded as such. 
3. 
If, at any level of decrease the platelet count is < 20,000/µL, this will be 
considered grade 4, unless the initial platelet count was ≤ 20,000 µL in which case the 
patient is unevaluable for toxicity referable to platelet counts. 
4. 
Baseline and subsequent hemoglobin determinations must be immediately prior 
to any given transfusions. 
5. 
If, at any level of decrease from the baseline value the platelet and/or hemoglobin 
counts are within normal limits, this will be considered a grade 0. 
 
* Hallek BD, et al.:  Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia 
updating the National Cancer-Institute- Working Group 1996 guidelines:  Blood 
111:54465456, 2008. 








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Appendix VI  Ibrutinib/Idelalsib Medication Diary 
CLL Arm only (Arm A or C) 
 
Name _________________ 
 
Mayo Clinic No_____________________ 
 
Patient Instructions 
 
• 
Your study doctor will tell you which medication (Ibrutinib or Idelalisib) will be added to your 
treatment regimen. 
• 
Please indicate on the calendar below every day that you take your medication by placing the 
dose taken on the line under the date.  
• 
If you miss a dose, place a check “0” under the date, but remember to take your prescribed dose 
at the next regularly scheduled time. 
• 
Bring all bottles and any unused study medication along with this diary when you return for your 
next appointment. 
• 
If you are receiving Ibrutinib, you should avoid eating grapefruit (including juice) and Seville 
oranges while on Ibrutinib. 
 
Medication(s) 
Dose  
Ibrutinib 
MG 
Idelalisib 
MG 
 
 
 
 
 
 
 
Date:__________________Participants Signature___________________________________ 
 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Ibrutinib/Idelalsib  
 
 
 
 
 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Ibrutinib/Idelalsib  
 
 
 
 
 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Ibrutinib/Idelalsib  
 
 
 
 
 
 


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Appendix VII   Inhibitors of CYP3A4/5 
A strong inhibitor increase the plasma AUC values by > 5-fold or reduces clearance by > 80%. Moderate 
inhibitors increases plasma clearance by > 2-fold or decreases clearance 50-80%. A strong inducer may 
decrease the plasma AUC more than 80% while a moderate inducer may reduce the plasma AUC 50-
80%. Sensitive substrates of CYP3A are designated as those with a > 5-fold increase in AUC when co-
administered with a known CYP3A inhibitor. A CYP3A substrate with a narrow therapeutic index refers 
to medication whose exposure-response relationship in the presence of CYP3A inhibitors may lead to 
serious safety concerns. 
The following lists are NOT to be considered as all inclusive. Providers should review the patient’s home 
medications and consult package inserts prior to initiation of Ibrutinib or Idelalisib for complete and 
updated information of cytochrome P450 inhibitor and inducer status. 
 
Strong Inhibitors of CYP3A4/5 
Boceprevir (Victrelis®)  
Clarithromycin (Biaxin®, Biaxin XL®)  
Conivaptan (Vaprisol®)  
Grapefruit juice  
Indinavir (Crixivan®)  
Itraconazole (Sporanox®)  
Ketoconazole (Nizoral®)  
Lopinavir/Ritonavir (Kaletra®)  
Nefazodone (Serzone®)  
Nelfinavir (Viracept®)  
Posaconazole (Noxafil®)  
Ritonavir (Novir®, Kaletra®)  
Saquinivir (Fortovase®, Invirase®)  
Telaprevir (Incivek®)  
Telithromycin (Ketek®)  
Voriconazole (Vfend®)  
 
Moderate Inhibitors of CYP3A4/5  
Aprepitant (Emend®)  
Atazanavir (Reyataz®)  
Ciprofloxacin (Cipro®)  
Darunavir (Prezista®)  
Delavirdine (Rescriptor®) 
Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®, Cardizem SR®, Cartia XT™, Dilacor 
XR®, Diltia XT®, Taztia XT™, Tiazac®)  
Erythromycin (Erythrocin®, E.E.S. ®, Ery-Tab®, Eryc®, EryPed®, PCE®  
Fluconazole (Diflucan®)  
Fosamprevnavir (Lexiva®)  
Imatinib (Gleevec®)  
Mifeprostone (Korlym®, Mifeprex®) 
Verapamil (Calan®, Calan SR®, Covera-HS®, Isoptin SR®, Verelan®, Verelan PM®) 
 
Strong Inducers of CYP3A4/5  
Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®)  
Phenytoin (Dilantin®, Phenytek®)  
Primidone (Mysoline®) 


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Protocol Version: October 1, 2020 
Rifampin (Rifadin®)  
Rifapentine(Priftin®) 
St. John’s wort  
 
Moderate Inducers of CYP3A4/5  
Bosentan (Tracleer®)  
Efavirenz (Sustiva®)  
Etravirine (Intelence®)  
Modafinil (Provigil®)  
Nafcillin  
Nevirapine (Viramune®)  
Phenobarbital (Luminal®)  
Rifabutin (Mycobutin®)  
Sensitive CYP3A substrates 
Alfentanil (Alfentanil®) 
Aprepitant (Emend®) 
Buspirone 
Conivaptan (Vaprisol®) 
Darifenacin (Enablex®) 
Darunavir (Prezista®)  
Dasatinib (Sprycel®)  
Dronedarone (Multaq®) 
Eletriptan (Relpax®) 
Eplerenone (Inspra®) 
Everolimus (Afinitor®, Zortress®) 
Felodipine (Plendil®) 
Indinavir (Crixivan) 
Lopinavir/Ritonavir (Kaletra®) 
Lovastatin (Altoprev®, Mevacor®) 
Lurasidone (Latuda®) 
Maraviroc (Selzentry®) 
Midazolam (Versed®) 
Nisoldipine (Sular®) 
Quetiapine (Seroquel®, Seroquel XR®) 
Saquinavir (Fortovase®, Invirase®) 
Sildenafil (Revatio®, Viagra®)  
Simvastatin (Zocor®) 
Sirolimus (Rapamune®) 
Tolvaptan (Samsca®) 
Tipranavir (Incivek®) 
Triazolam (Halcion ®) 
Vardenafil (Levitra ®, Staxyn®) 
 
CYP3A substrates with narrow therapeutic range 
Cyclosporine (Gengraf®, Neoral®, SanIMMUNE®) 
Dihydroergotamine (Migranal®) 
Ergotamine (Ergomar®) 
Fentanyl (Abstral®, Actiq®, Duragesic®, Fentora®, Ionsys®, Lazanda®, Onsolis®, Subsys®) 
Pimozide (Orap®) 
Quinidine 


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Sirolimus (Rapamune®) 
Tacrolimus (Prograf®)