A Phase II Study Of Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
Phase: PHASE2
Conditions: B-Cell Chronic Lymphocytic Leukemia, B-Lymphocytic Leukemia, Chronic, Chronic Lymphocytic Leukemia, Leukemia, Chronic Lymphatic, Leukemia, Chronic Lymphocytic, B-Cell, Leukemia, Lymphocytic, Chronic, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic Leukemia, Chronic, B Cell, Lymphocytic Leukemia, Chronic, B-Cell
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
A Phase II Study of Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or 
Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic 
Lymphoma (CLL/SLL) 
NCT number: 
 
NCT03204188 
Document Type:  
Protocol with Statistical Analysis Plan (SAP)  
Document Date: 
July 20, 2022 
 
 

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Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
1
CLINICAL RESEARCH PROJECT
Protocol #: 17-H-0118
Drug Names: Ibrutinib, Fludarabine, Pembrolizumab
IND: Ibrutinib (113752)
Title: A Phase II Study of Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) 
Short Title: Simultaneous targeting of B and T cells in CLL
Keywords: Ibrutinib, Fludarabine, Pembrolizumab, BTK Inhibitor, Checkpoint Inhibitor, CLL, SLL
 
Principal Investigator:
Adrian Wiestner, M.D., Ph.D.,  HB, NHLBI (E)
Hematology  Branch
National Heart, Lung, and Blood Institute 
Building 10, Rm 3-5140
10 Center Drive
Bethesda, MD 20892
Phone: 301-594-6855
E-mail: wiestnea@nhlbi.nih.gov
Company Providing Investigational Drug: Merck; Pharmacyclics, an Abbvie Company
Subjects of Study:
Number 
Sex 
Age-range 
25 evaluable
M/F
> 18
(Accrual Ceiling 30, to account for ineligible subjects)
Ionizing Radiation for Research:
Yes
Off-Site Project: 
No
Multi-center trial:
No
DSMB Involvement:
Yes

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Amendment N, July 20, 2022
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PRÉCIS
Background:

Chronic lymphocytic leukemia and small lymphocytic lymphoma (hereby referred to as CLL) are 
tumors of B cells. A subset of patients categorized as high-risk CLL has unfavorable outcomes when 
treated with conventional chemotherapy. High-risk CLL is defined by relapsed/refractory disease 
status, or the presence of high-risk genetic changes, such as deletion 17p and aberrations affecting 
TP53, NOTCH1, SF3B1 and MYC genes. Studies have indicated two critical factors are required for 
the proliferation of CLL cells. First, CLL cells grow and survive because they receive signals through 
the B-cell receptor (BCR). Second, CLL cells benefit from interactions with other immune cells, 
especially T cells.

The stimulation through the BCR can be blocked by ibrutinib, which is an oral drug that selectively 
inhibits Bruton’s tyrosine kinase. In clinical trials, ibrutinib demonstrated safety and high response 
rates in patients with high-risk disease. Ibrutinib has gained FDA approval as a treatment for CLL 
regardless of prior treatment or cytogenetic status. However, single-agent ibrutinib has limitations; 
the drug does not eliminate all tumor cells and, with time, the tumor cells may become resistant. 
Therefore, combination of ibrutinib with other drugs could be beneficial. 

This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of 
CLL. Fludarabine is a well-tolerated drug that has been used widely to treat CLL. Also, fludarabine 
can kill both malignant B cells and T cells that support the growth of leukemia cells. Pembrolizumab 
targets immune checkpoint molecules and enhances the cell-killing activity of T cells. With this 
approach we aim to achieve a greater reduction in CLL cells than with single agent ibrutinib and 
restore healthier immune system that could contribute to durable responses.
Objectives:

To investigate the rate of complete response to ibrutinib, short course fludarabine and 
pembrolizumab.
Key eligibility criteria:

Patients with CLL meeting treatment indications per iwCLL guidelines.

High-risk disease defined by one of the following:
o Relapsed/refractory disease 
OR
o High-risk genetic changes: deletion 17p, TP53 or NOTCH1 or SF3B1 mutation, MYC 
aberration, or complex cytogenetics.
Design:

This is a single-arm, open-label phase 2 study. 

Timeline: Treatment on this study is given in cycles from cycle -3 to 17, then in months beyond cycle 
17. Cycles -3 to -1 are 28-day cycles. Cycles 1 to 17 are 21-day cycles. After completion of 1 year of 
pembrolizumab, the time on study is by chronological months on study from starting pembrolizumab. 

Treatment plan: Ibrutinib is given daily until disease progression or intolerable side effects occur. 
Fludarabine is given on cycle -2 only. Pembrolizumab is given every 3 weeks starting from cycle 1 

17-H-0118
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Amendment N, July 20, 2022
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for 1 year. Minimal residual disease will be measured at 2 years from cycle 1 to determine the need 
for long-term treatment with ibrutinib.

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Amendment N, July 20, 2022
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1.0
OBJECTIVES ................................................................................................................................................7
1.1
PRIMARY OBJECTIVE.....................................................................................................................................................7
1.2
SECONDARY OBJECTIVES ...............................................................................................................................................7
2.0
BACKGROUND & RATIONALE.................................................................................................................7
2.1
PATHOPHYSIOLOGY .....................................................................................................................................................7
2.2
EPIDEMIOLOGY...........................................................................................................................................................7
2.3
DIAGNOSIS ................................................................................................................................................................8
2.4
STAGING AND OTHER PROGNOSTIC CATEGORIES ................................................................................................................8
2.5
INDICATIONS OF TREATMENT .........................................................................................................................................9
2.6
TREATMENT OPTIONS...................................................................................................................................................9
2.6.1
Watchful waiting ............................................................................................................................................9
2.6.2
Frontline chemoimmunotherapy ..................................................................................................................10
2.6.3
Salvage chemoimmunotherapy....................................................................................................................10
2.6.4
Stem cell transplant......................................................................................................................................11
2.6.5
Targeted agents............................................................................................................................................11
2.7
CLINICAL AND SCIENTIFIC JUSTIFICATION FOR PROTOCOL DESIGN.........................................................................................12
2.7.1
Limitations of currently available treatment options ...................................................................................12
2.7.2
Rationale for simultaneous B- and T-cell targeting ......................................................................................13
2.7.3
Preliminary data on lymphocyte dynamics...................................................................................................14
2.8
PEMBROLIZUMAB......................................................................................................................................................15
2.8.1
Mechanism of Action....................................................................................................................................15
2.8.2
Pharmacokinetics..........................................................................................................................................16
2.8.3
Metabolism and Clearance...........................................................................................................................17
2.8.4
Summary of clinical efficacy and safety........................................................................................................17
2.9
IBRUTINIB................................................................................................................................................................18
2.9.1
Pharmacokinetics and product metabolism .................................................................................................18
2.9.2
Summary of clinical safety............................................................................................................................19
3.0
STUDY DESIGN..........................................................................................................................................20
4.0
ELIGIBILITY ASSESSMENT AND ENROLLMENT ...............................................................................20
4.1
INCLUSION CRITERIA..................................................................................................................................................20
4.2
EXCLUSION CRITERIA..................................................................................................................................................22
5.0
TREATMENT PLAN...................................................................................................................................23
5.1
DRUG ADMINISTRATION AND TREATMENT SCHEDULE........................................................................................................23
5.2
PROPHYLACTIC MEDICATIONS ......................................................................................................................................25
5.3
DOSE MODIFICATION GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS...............................................................................25
5.3.1 Table 5. Cytopenia ............................................................................................................................................25
5.3.2 
Atrial fibrillation .......................................................................................................................................25
5.3.3
Hepatic impairment......................................................................................................................................26
5.3.4
Other non-hematologic toxicities .................................................................................................................27
5.4
HOLDING OF STUDY DRUG ADMINISTRATION...................................................................................................................31
5.4.1
Ibrutinib and surgical procedures .................................................................................................................31
5.4.2
Medically necessary conditions to hold study drugs.....................................................................................31
5.4.3
Permanent discontinuation of study drug administration in case of treatment related adverse events .....31
5.5
SUPPORTIVE CARE (NON-INVESTIGATIONAL) ...................................................................................................................32
5.6
PERMITTED AND NON-PERMITTED CONCOMITANT MEDICATIONS ........................................................................................32
5.6.1  
Guideline for the use of CYP3A inhibitors/inducers..................................................................................32
5.6.3 
Concomitant use of antiplatelet agents and anticoagulants ...................................................................33
5.6.4 
Concomitant use of systemic glucocorticoids...........................................................................................33
5.6.5 
Prohibited concomitant medications .......................................................................................................33
5.7
SPECIAL INSTRUCTIONS...............................................................................................................................................33

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Amendment N, July 20, 2022
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5.7.1
Immunizations: .............................................................................................................................................33
5.7.2
Birth control:.................................................................................................................................................33
5.7.3 GUIDELINES FOR RESCUE MEDICATIONS AND SUPPORTIVE CARE ..........................................................................................34
5.7.4
Immune-Infusion reactions...........................................................................................................................34
6.0
CLINICAL MONITORING (SEE APPENDIX A. SCHEDULE OF EVENTS)..........................................35
6.1
STUDY EVALUATIONS: SCREENING AND BASELINE............................................................................................................35
6.2
ON THERAPY EVALUATIONS .........................................................................................................................................37
6.3
RESPONSE ASSESSMENT..............................................................................................................................................38
6.4
AT PROGRESSION EVALUATION.....................................................................................................................................39
7.0
CRITERIA FOR RESPONSE......................................................................................................................39
8.0
ANCILLARY LABORATORY RESEARCH STUDIES.............................................................................41
8.1
COLLECTION OF SAMPLES............................................................................................................................................41
8.2
INTENDED USE..........................................................................................................................................................41
8.3
GENOMIC TESTING ....................................................................................................................................................41
8.4
STORAGE, TRACKING AND DISPOSITION OF SAMPLES AND DATA ..........................................................................................43
9.0
BIOSTATISTICAL CONSIDERATIONS...................................................................................................43
9.1
PRIMARY ENDPOINT...................................................................................................................................................43
9.2
SECONDARY ENDPOINTS .............................................................................................................................................43
9.3
SAMPLE SIZE ............................................................................................................................................................44
9.4
STATISTICAL METHODS...............................................................................................................................................44
9.5
STUDY STOPPING RULES.............................................................................................................................................44
9.6
STOPPING RULE FOR MORTALITY..................................................................................................................................45
9.7
OFF STUDY CRITERIA (FOR SUBJECT PARTICIPATION).........................................................................................................46
10.0 DATA AND SAFETY MONITORING........................................................................................................47
10.1 ASSESSMENT OF SAFETY .............................................................................................................................................47
10.1.1.   Severity.........................................................................................................................................................47
10.1.2
Pregnancy.................................................................................................................................................48
10.1.4
Causality assessments..............................................................................................................................49
10.2 DOCUMENTATION  AND MANAGEMENT OF DATABASE ......................................................................................................49
10.3 NIH INTRAMURAL IRB AND CD REPORTING ...................................................................................................................50
10.4 REPORTS TO MERCK ..................................................................................................................................................50
10.5 REPORTS TO PHARMACYCLICS LLC, AN ABBVIE COMPANY ................................................................................................51
10.6 REPORTING PERIOD FOR AES.......................................................................................................................................51
10.7 REPORTING FOR OTHER MALIGNANCIES .........................................................................................................................51
10.8 
Events of clinical interest ..............................................................................................................................51
10.9 DATA MANAGEMENT .................................................................................................................................................52
10.10        PROTOCOL AMENDMENTS .....................................................................................................................................53
10.11 PROTOCOL MONITORING ...........................................................................................................................................53
11.0 HUMAN SUBJECT PROTECTION ...........................................................................................................54
11.1 RATIONALE FOR SUBJECT SELECTION..............................................................................................................................54
11.1.1
Predicted distribution by gender, age and race........................................................................................54
11.1.2
Special Populations ..................................................................................................................................54
11.2 RISKS AND DISCOMFORTS RELATED TO RESEARCH.............................................................................................................56
11.2.1
Risks related to Ibrutinib ..........................................................................................................................56
11.2.2
Risks related to fludarabine......................................................................................................................61
11.2.3
Risks related to pembrolizumab...............................................................................................................61
11.2. 3
  Risks related to blood draws...................................................................................................................63
11. 2. 4 
  Risks related to CT Scan......................................................................................................................63
11. 2. 5
Risks related to pregnancy and nursing mothers .....................................................................................64

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Amendment N, July 20, 2022
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11. 2. 6 
Risks related to bone marrow biopsy...................................................................................................64
11.3 RISKS IN RELATION TO BENEFIT....................................................................................................................................64
11.4 INFORMED CONSENT PROCESSES AND PROCEDURES..........................................................................................................64
11.5 CONFLICT OF INTEREST ...............................................................................................................................................65
11.6 TECHNICAL TRANSFER AGREEMENTS.............................................................................................................................65
12.0 PHARMACEUTICALS ...............................................................................................................................65
12.1 IBRUTINIB................................................................................................................................................................65
12.2 FLUDARABINE:..........................................................................................................................................................66
12.3 PEMBROLIZUMAB......................................................................................................................................................67
12.4 ACCOUNTABILITY PROCEDURES ....................................................................................................................................68
13.0 REFERENCES.............................................................................................................................................69
APPENDIX A:  Schedule of Events 
APPENDIX B:  Inhibitors and Inducers of CYP3A
APPENDIX C:  Child-Pugh Score for Subjects with Liver Impairment

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Amendment N, July 20, 2022
7
1.0
OBJECTIVES 
1.1
Primary objective

To test the rate of complete response of the combination of ibrutinib, fludarabine, and pembrolizumab 
in patients with high-risk and/or relapsed/refractory chronic lymphocytic leukemia (CLL) and small 
lymphocytic leukemia (SLL)
1.2
Secondary objectives 

Tolerability of the combination regimen

Overall response rate (ORR)

Duration of response (DOR)

Best response

Minimal residual disease (MRD) status

Progression-free survival (PFS)

Overall survival (OS)

To explore the biologic effects on B- and T-cell subsets and function

To identify predictors of clinical response 
2.0
BACKGROUND & RATIONALE
2.1
Pathophysiology
CLL is characterized by clonal proliferation of auto-reactive B cells mediated by B cell receptor (BCR) 
signaling. The BCR is a multimeric complex formed by the assembly of surface immunoglobulin (Ig) 
homodimer and Igα/Igβ (CD79a/CD79b) heterodimer. Engagement of antigen at BCR phosphorylates 
immunoreceptor tyrosine-based activation motifs (ITAM) motif and links Ig chains to intracellular Src family 
tyrosine kinases. Activation of BCR signaling leads to downstream activation of Bruton tyrosine kinase 
(BTK).1 Therefore, BTK is an important therapeutic target for BCR-addicted leukemic B cells.
The second key component of CLL pathogenesis is a bidirectional interaction between tumor and 
microenvironment. T cells in tumor microenvironment have a stimulatory role for the survival of CLL cells. 
In vitro, apoptosis of CLL cells can be rescued by stromal cell co-culture or by the addition of soluble 
factors.2,3 In human, T and leukemic B cells aggregate to form ‘proliferation centers’ within bone marrow 
(BM) and lymphoid tissues, where these rallied cells form immune synapses.4 CD40 ligand form a crosstalk 
between T and CLL cells which stimulates leukemic B cell survival and promotes resistance to apoptosis.5,6 In 
addition, T cells in CLL are functionally4 and phenotypically7 defective, and allow malignant B cells to 
escape immune surveillance. “Pseudo-exhaustion” of effector T cells is explained by increased expression of 
immune checkpoints on CLL cells4,8 and by increased number of regulatory T cells in CLL patients.9 
2.2
Epidemiology
CLL is the most common leukemia of adults in Western countries with an annual incidence of 2-4.5 per 
100,000 in general population. North American Association of Central Cancer Registries estimated that 
14,620 men and women to be newly diagnosed with CLL in 2015.10 CLL affects males more frequently than 
females.   It is a disease of older individuals with the median age of 73 years for Caucasian.11 Incidences vary 
by ethnicity. The highest incidence is seen in Caucasians, followed by African Americans, and it is much 
lower in Asians and Hispanics.

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Amendment N, July 20, 2022
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2.3
Diagnosis
2008 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid 
Tissues defines CLL as an absolute count of >5.0x109 monoclonal B cells/L with a CLL immunophenotype in 
the peripheral blood (PB), if there is an absence of disease-related symptoms or cytopenia, or tissue 
involvement other than BM.12 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
criteria uses two criteria to be met for the diagnosis of CLL:13 

The presence of at least 5x109/L morphologically mature-appearing small lymphocytes in the PB.

Circulating monoclonal B lymphocytes defined by PB flow cytometry. The characteristic pattern of 
CLL immunophenotype is: expression of the T-cell surface antigen (CD5), expression of B-cell 
surface (CD19, CD20, and CD23), and low-level expression of surface Ig with either κ or λ (but not 
both) light chains.
Diagnosis of small lymphocytic lymphoma (SLL) requires the presence of lymphadenopathy and/or 
splenomegaly confirmed by histopathologic confirmation through lymph node (LN) biopsy when possible, 
while having < 5x109 circulating monoclonal B cells/L. For the purposes of this study, the term “CLL” will 
encompass both CLL and SLL.
2.4
Staging and other prognostic categories
There are two prognostic staging systems in CLL called Rai and Binet. Rai staging allows stratification of 
patients into five distinct prognostic groups (Table 1).14
Table 1. Rai staging system
Stage
Risk
Manifestation
Median survival 
(months)
0
Low
Lymphocytosis
120
I
Lymphocytosis with adenopathy
108
II
Intermediate
Lymphocytosis with hepatomegaly or splenomegaly
94
III
Lymphocytosis with anemia (Hemoglobin < 11g/dL)
60
IV
High
Lymphocytosis with thrombocytopenia (Platelet < 100K/µL)
60
The limitation of Rai staging is underestimation of the risk of progression in early stages of disease. For this 
reason, various prognostic markers have been developed to identify patients with aggressive clinical 
phenotype. Prognostic markers predictive of poor clinical outcome include the presence of unmutated 
immunoglobulin variable heavy chain gene (IGHV-U),15 ξ (zeta)-chain associated protein-70 (ZAP-70),16 
CD38, lymphocyte doubling time (LDT),17 BM histologic pattern,18  β-2 microglobulin,19 and complex 
cytogenetics.20
Among many markers, detection of cytogenetic abnormalities with fluorescence in situ hybridization (FISH) is 
widely used for risk stratification (Table 2).21 Deletion 17p, found in 7-10% of newly diagnosed CLL, predicts 
the worst prognosis. The poor prognosis of deletion 17p is attributable to the functional loss of TP53 tumor 
suppressor gene mapped at the deleted loci. 
Table 2. Cytogenetic Abnormalities in CLL
Chromosome
Median survival 
(months)
Median time to first treatment
(months)

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Amendment N, July 20, 2022
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Deletion 17p13
32
9
Deletion 11q22-23
79
13
Trisomy 12
114
49
Normal
111
33
Deletion 13q14
133
92
More recently, whole genome and exome sequencing have revealed complex mutational landscapes of CLL and 
the prognostic impact of several driver mutations.22,23 NOTCH1 mutation, for instance, is found in 10% of newly 
diagnosed CLL and is predictive of shorter survival compared to the wild-type (OS: 79.2 months with NOTCH1 
mutation vs. not-reached with NOTCH1 wild-type).24 Similarly, SF3B1 mutation is associated with poorer 
clinical outcome compared to the wild-type.24 TP53 mutation is an independent factor predictive of unfavorable 
outcome in CLL.25 MYC aberration is characterized by an aggressive clinical phenotype with median survival 
from genetic detection of 19 months.26
2.5
Indications of treatment
Newly diagnosed patients with asymptomatic early stage disease (Rai 0, Binet A) should be monitored without 
intervention unless there is an evidence of rapid disease progression.27 Symptomatic patients with advanced 
stage (Rai 3 or 4, Binet B or C) stages usually benefit from treatment. 2008 IWCLL defines active disease by 
following criteria:13

Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia 
and/or thrombocytopenia 

Massive (i.e., at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 

Massive (i.e., at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy 

Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte 
doubling time (LDT) of less than 6 months. LDT can be obtained by linear regression extrapolation of 
absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 
months. In patients with initial blood lymphocyte counts of less than 30x109/L (30,000/µL), LDT 
should not be used as a single parameter to define a treatment indication. In addition, factors 
contributing to lymphocytosis or lymphadenopathy other than CLL (i.e., infections) should be excluded. 

Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other 
standard therapy

Constitutional symptoms, defined as any one or more of the following disease-related symptoms or 
signs:
o
Unintentional weight loss of 10% or more within the previous 6 months; 
o
Significant fatigue (i.e., ECOG performance status 2 or worse; inability to work or perform usual 
activities); 
o
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of infection; or 
o
Night sweats for more than 1 month without evidence of infection.
2.6
Treatment options
2.6.1
Watchful waiting
Asymptomatic early stage disease should be monitored without intervention until disease progression.13 During 
the observation period, patients are periodically assessed for the evidence of progressive disease based on 
symptoms, physical exam and laboratory evaluations. 

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Amendment N, July 20, 2022
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2.6.2
Frontline chemoimmunotherapy
Treatment for CLL should be individualized based on host and biological factors, including fitness of a patient, 
comorbidities, disease burden, and cytogenetic features. 
Alkylating agents, purine analogues and monoclonal antibodies have different mechanisms of action and 
toxicity profiles. Combinations of different classes of drugs have improved treatment efficacy in CLL. In 
previously untreated and medically fit CLL population, ORR was 90% with the combination of fludarabine, 
cyclophosphamide, and rituximab (FCR),28 and 88% with bendamustine and rituximab (BR).29 Efficacy and 
safety of frontline BR and FCR are being directly compared in an ongoing randomized phase III trial by the 
German CLL Study Group.30 Interim report showed identical ORR and similar survival between FCR and BR, 
while PFS and the depth of response were better in the FCR arm.
Other regimens investigated in CLL are; cladribine plus rituximab, methylprednisolone plus rituximab, 
fludarabine plus alemtuzumab, and fludarabine, cyclophosphamide plus alemtuzumab. None of these regimens 
resulted in efficacy comparable to FCR.31 There are second generation of anti-CD20 monoclonal antibodies 
including obinutuzumab and ofatumumab. Obinutuzumab plus chlorambucil showed survival benefit compared 
to chlorambucil alone, and resulted in superior ORR and PFS compared to rituximab plus chlorambucil in 
previously untreated elderly CLL patients.32 
The major limitation of conventional chemoimmunotherapy is toxicity. High efficacies of FCR or BR regimens 
occur at the expense of short- and long-term adverse events and, at times, mortality. Rates of treatment-related 
mortality are 3.9% with FCR and 2.1% with BR.30 More than 90% of patients treated with FCR and 78.5% 
treated with BR experience moderate to severe adverse events equivalent to CTCAE Grade 3 to 5.30 
Hematologic toxicities such as severe neutropenia can occur while on treatment (81.7%) or after treatment 
completion.33 Infusional reactions related to monoclonal antibodies also limit the successful delivery of 
treatment. As a part of long-term toxicities, secondary malignancy can occur after being exposed to alkylating 
agents. Intergroup E2997 trial reported 8.2% cumulative incidence of myeloid neoplasia at 7 years after 
treatment with fludarabine plus cyclophosphamide (FC).34 
The other critical limitation of conventional chemoimmunotherapy is the lack of efficacy with the presence of 
high-risk mutations. Patients with deletion 17p have inferior overall and depth of responses compared to the 
overall CLL population after FCR.28 In addition to FISH-defined high-risk disease, the presence of TP53 or 
NOTCH1 mutation detected by targeted sequencing predicts inferior survival after FCR.24 Response to the BR 
regimen is by far inferior in a cohort with 17p deletion (37.5%) than in the overall population (88%).29 While 
alemtuzumab-based chemoimmunotherapy increased ORR in 17p deletion to 75-88%, the benefit of high 
efficacy was offset by toxicity.35,36 The rate of opportunistic infection increases by 2.5-fold after the addition 
of alemtuzumab to FC, and is poorly tolerated among elderly patients.35 
2.6.3
Salvage chemoimmunotherapy
In spite of intensive chemoimmunotherapy, approximately half of the patients treated with frontline FCR return 
with relapsed and/or refractory diseases.37 Relapsed/refractory CLL is incurable in most cases and requires 
multiple lines of salvage treatment. 
Conventional chemotherapy options for relapsed/refractory CLL encompass aforementioned regimens. An 
early study using salvage FCR reported high ORR of 73%.38 However, the majority of the study population was 
fludarabine-sensitive (61%) and rituximab-naïve (81%), which are no longer the features of the 

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Amendment N, July 20, 2022
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relapsed/refractory population due to the frequent frontline use of a purine analog and rituximab. The presence 
of fludarabine-refractory disease, deletion 17p, or more than 3 prior treatments predict shorter survival.39 BR is 
an alternative treatment option, which resulted in ORR of 59% in a multicenter phase II trial of 78 
relapsed/refractory CLL.40 However, the duration of response with BR was short-lived (median event-free 
survival (EFS): 14.7 months). Ofatumumab was approved by the U.S. FDA in 2009 for CLL refractory to both 
fludarabine and alemtuzumab, based on the ORR of 47-58% in the heavily pre-treated CLL population.38 While 
various chemotherapy regimens are available for relapsed/refractory CLL patients, many have accompanying 
toxicities, and durable remissions are rare. Prior to the advent of BCR targeted agents, the goal of salvage 
chemotherapy in CLL was to bridge patients into next treatment or to reduce tumor burden before hematopoietic 
stem cell transplant.
2.6.4
Stem cell transplant 
Allogeneic hematopoietic stem cell transplant remains as the sole curative option for CLL to date. However, 
only a selected subset of patients can be transplant candidates due to the advanced age of the population (median 
age at diagnosis: 72),41 comorbidities, and limitations inherent to the search for optimal stem cell donors. 
Despite transplant platforms using reduced-intensity conditioning and improved supportive care, non-relapse 
mortalities in CLL still ranges from 16 to 27% in 3-5 years after transplant.42 Transplant is currently reserved 
for a small subset of patients with an available donor, good performance status, minimal comorbidities, and 
high-risk features. 
2.6.5
Targeted agents 
BCR signaling is a critical survival signal for malignant B cells. Orally bioavailable kinase inhibitors, such as 
ibrutinib and idelalisib, can effectively target downstream kinases involved in BCR signaling. 
Ibrutinib
Once daily administration of ibrutinib causes sustained inactivation of BTK in malignant B cells.43,44 The phase 
1b/2 trial in 85 relapsed CLL treated with either 420 mg or 840 mg of ibrutinib demonstrated ORR of 71% in 
both dosing groups with an additional 15-20% with a partial response with lymphocytosis (PR-L).45 Ibrutinib 
was compared to ofatumumab in a phase III randomized trial, which showed superior ORR (42.6% vs. 4.1%, 
p<.001) and survival (12-month OS: 90% vs. 79%, hazard ratio 0.43, p=.005) of the ibrutinib arm.46 Responses 
to ibrutinib appear to be independent of clinical and genomic risk factors. In the elderly CLL population of age 
65 years or older, ibrutinib was an effective and well-tolerated initial therapy.47 In the high-risk CLL population 
with TP53 mutation, treatment with a single-agent ibrutinib led to an unprecedented response rate of 97%.48 
Ibrutinib is approved by the U.S. FDA for the treatment of CLL patients regardless of prior therapy or cytogenic 
status.
Ibrutinib has been investigated in combinations with chemoimmunotherapy. Ibrutinib was combined with 
rituximab,49 ofatumumab,50 FCR or BR51 in early studies, which appeared to be tolerable and have an improved 
depth of response. However, an ongoing randomized phase III study comparing BR with or without ibrutinib 
did not fully translate the promising results of early phase studies. Combination of ibrutinib and 6 cycles of BR 
led to ORR of 83% and CR of 10%,52 which were comparable to the efficacy of a single-agent ibrutinib (ORR 
of 90%, CR of 7%).46 There is an ongoing randomized study comparing ibrutinib-based combination to ibrutinib 
alone, which will define the role of chemotherapy in the era of targeted agents.53 
Idelalisib

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Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
12
Idelalisib selectively inhibits p110δ isoform of PI3K. A phase I study enrolled 54 heavily pretreated 
relapsed/refractory CLL patients, and demonstrated ORR of 73% with 6 different dose levels of oral idelalisib 
(range: 50-350mg once or twice daily).54 The highest median PFS was seen in patients receiving 150mg twice 
daily or greater (median PFS: 29 months), and no dose-limiting toxicities was observed. Using the 150mg twice 
daily dosing, the combination of idelalisib and rituximab was compared to placebo and rituximab in a 
randomized phase III trial.55 The idelalisib arm had a higher ORR (81% vs. 13%, p<0.001) and 12-month OS 
(92% vs. 80%, p=0.02) compared to the placebo arm. Idelalisib was FDA approved in 2014 for the treatment 
of patients with relapsed CLL, in combination with rituximab, for whom rituximab alone would be considered 
appropriate therapy due to other co-morbidities, and for patients with SLL who have received at least two prior 
systemic therapies. 
Venetoclax
CLL has dysfunctional intrinsic apoptotic pathways due to the mutation of genes encoding pro-apoptotic 
proteins, such as p53, or due to overexpression of anti-apoptotic proteins, such as Bcl-2. Venetoclax (ABT-
199) is a potent, orally bioavailable, small molecule inhibitor of Bcl-2 that induces apoptosis.56 A phase I study 
with venetoclax led to deep and durable remissions in 84 patients with relapsed/refractory CLL (CR or CRi in 
22%).57 The most common adverse events were diarrhea (46%), neutropenia (43%), fatigue (34%), upper 
respiratory tract infection (29%), and cough (25%). Notably, early studies reported an 11% incidence of grade 
3-4 tumor lysis syndrome, which decreased to <5% after dose modification with a ramp-up schedule adopted 
for later studies. Venetoclax is approved for treatment of CLL patients, with or without deletion 17p, who have 
received at least one line of therapy.
2.7
Clinical and scientific justification for protocol design
2.7.1
Limitations of currently available treatment options
A subset of CLL patients is at an increased risk of poor clinical outcome when treated with 
chemoimmunotherapy. High-risk CLL is defined by the relapsed/refractory disease status, or by presence of 
high-risk cytogenetic mutations, such as deletion 17p, TP53, and NOTCH1. ORR and PFS in the subgroup with 
deletion 17p are inferior compared to those in overall CLL population (Table 3). Poor prognosis of deletion 
17p persists in spite of the addition of anti-CD20 monoclonal antibodies.
        Table 3. Comparison of response: all studied CLL vs. subgroup with deletion 17p
Regimen
Ref
N,
all studied
N,
17p-
ORR,
all studied (%)
ORR,
17p- (%)
PFS,
all studied
PFS,
17p-
 Treatment-naïve
 FC
28
409
29
88
34
45% at 3 years
0% at 3 years
 FCR
28
408
22
95
68
65% at 3 years
18% at 3 years
 BR
29
117
8
88
37.5
33.9 months*
NA
 Relapsed/refractory
 FCR
39
284
20
74
35
20.9 months**
5 months**
 Ibrutinib
58
132
36
89
79
76% at 30 months
48% at 30 months
BR
Bendamustine, rituximab
FC
Fludarabine, cyclophosphamide

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Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
13
FCR
Fludarabine, cyclophosphamide, rituximab
NA
Not assessed
PFS
Progression-free survival
Ref
References
17p-
Deletion 17p
*
Median event-free survival
**
Median progression-free survival
BCR inhibitors improved the treatment outcome of high-risk CLL to an unprecedented level. Treatment with a 
single-agent ibrutinib led to ORR of 82.6% and 12-month PFS of 79.3% in 144 relapsed/refractory CLL with 
deletion 17p.59 At the NHLBI, Farooqui et al. reported 51 patients with either deletion 17p or TP53 mutation 
treated with ibrutinib.48 ORR (94% at 24 weeks) and PFS (82% at 24 months) were higher in this trial, which 
was attributable to the study population mix of previously untreated and relapsed/refractory diseases. Ibrutinib 
is approved by the U.S. FDA for the treatment of CLL patients regardless of prior treatment or the status of 
deletion 17p.
Nevertheless, accumulating clinical experiences revealed several limitations of targeted agents. First, poor 
prognosis of the high-risk subgroup is not fully overcome by targeted agents. Long-term follow up data of 
single-agent ibrutinib clearly shows the inferior rate and shorter duration of response with the presence of 
deletion 17p (Table 3). Second, deep responses are infrequent. CR was reported in 2% of relapsed/refractory 
CLL45 and 4-13% of previously untreated CLL.47,60 When ibrutinib was combined with other agents, the CR 
rate minimally increases to 8% (ibrutinib/rituximab)49 and 10% (ibrutinib/bendamustine/rituximab).52 The lack 
of deep response mandates the continued use of targeted agents, which increases the risk of long-term toxicities 
and poses a significant financial burden on health care. Third, drug resistance can develop during treatment 
with a single-agent ibrutinib. Acquired mutations at the drug binding site of BTK or its downstream target 
called phospholipase C-gamma 2 (PLCγ2) were identified in patients who developed secondary resistance to 
ibrutinib.61,62 Clinical outcome of patients who present with disease progression or transformation while on 
ibrutinib is extremely poor, and their median survival was reported to be only 3 months.63 These limitations call 
for a novel treatment approach that is both efficacious and safe for high-risk CLL population.
2.7.2
Rationale for simultaneous B- and T-cell targeting
CLL is a clonal proliferation of auto-reactive B cells that escape immune surveillance. BCR activation generates 
a critical survival signal for malignant B cells, and is pharmacologically targetable with ibrutinib.43 However, 
single-agent ibrutinib has limitations; the drug does not eliminate all the tumor cells and, with time, resistance 
can emerge - more commonly in high-risk CLL. 
T cells interact with and support the survival of malignant B cells. Apoptosis of CLL cells can be rescued by 
stromal cell co-culture or by the addition of soluble factors.3 Elimination of T cells in vivo was shown to be 
sufficient to abrogate CLL cell growth.64 CD40 ligand forms a crosstalk between T and CLL cells, which 
stimulates CLL survival and promotes resistance to apoptosis.5,6 Fludarabine is a biologically plausible addition 
to ibrutinib for it can effectively reduce T cell help in CLL pathogenesis, and has been widely used as a 
conditioning agent in immunotherapies. 
CLL cells escape endogenous immune surveillance due to functionally and phenotypically defective effector T 
cells and due to immune regulatory signals from Treg.9 Among many signals suppressing cytotoxic anti-tumor 
activity, PD-L1 is a key immune checkpoint molecule overexpressed by CLL cells and myeloid dendritic cells 
within the microenvironment.4,65,66 Preclinical studies have shown an animal model can recapitulate human 
CLL with an increased PD-1/PD-L1 expression in T cells and decreased effector function of CD8+ T cells.67 

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Amendment N, July 20, 2022
14
Blockade of PD-1/PD-L1 axis led to reduction of CLL from lymphoid tissues, decreased inflammatory 
cytokines, and restored effector T cell phenotype in vivo and ex vivo.68 PD-1 can be effectively blocked by 
pembrolizumab, an anti-PD-1 monoclonal antibody. Pharmacologic properties of pembrolizumab are further 
discussed under section 2.8 Pembrolizumab.
We hypothesize simultaneous targeting of B and T cells can augment the depth and the duration of responses, 
and the addition of pembrolizumab to ibrutinib and fludarabine can help restore immune surveillance against 
the tumor. To achieve this aim, three agents are needed to modulate B and T cells. First, ibrutinib is given daily 
for continued BCR inhibition. Second, a short-course fludarabine is added prior to the introduction of 
pembrolizumab with aims to reconstitute a favorable microenvironment for effector T cells and minimize 
immune-related toxicities of pembrolizumab. Third, pembrolizumab is added later to restore cytotoxic function 
of effector T cells. 
2.7.3
Preliminary data on lymphocyte dynamics
Both published data from outside and preliminary data from our institutional experience with fludarabine-based 
regimen supports lymphocyte modulatory role of fludarabine. First, fludarabine effectively reduces regulatory 
T cells in CLL.9 Accumulating preclinical data support the key role of regulatory T cells in T cell exhaustion. 
In a mouse model infected with lymphocytic choriomeningitis virus (LCMV), ablation of regulatory T cells 
was able to rescue exhausted T cells, expanded virus-specific CD8+ T cells, and up-regulated expression of 
PD-L1.69 Simultaneous treatment with PD-L1 blockade and CD4+ T cell depletion led to superior viral control 
in the LCMV mouse model.70 Second, fludarabine removes inhibitory signals on effector T cells. Given that 
untreated CLL has dramatically increased CD8+ T cells, reduction of abnormal T cell population may be 
important to prior to the addition of pembrolizumab. After fludarabine-based chemoimmunotherapy, CD4+ and 
8+ T cells initially decrease (Figure 1) then gradually return to the lower normal range within 6 months to 1 
year (Figure 2). Incremental recovery of the number of effector T cells may be critical to reduce potential 
toxicities related to autoimmune flare. Another benefit obtained by a lead-in phase with ibrutinib and 
fludarabine is a proportional recovery of effector T cells (Figure 2). Treatment with conventional 
chemoimmunotherapy reduces the tumor burden, which in turn elevates the proportion of CD8+ cells per 
absolute lymphocytes. 
In summary, fludarabine, a purine analog cytotoxic to both B and T cells,71-73 can help reduce regulatory T cells 
while increasing the ratio of effector T cells. Safety of fludarabine is justified by a large body of experience in 
CLL. 
Figure 1. Absolute numbers of CD4+ and CD8+ T cells after 3 cycles of fludarabine-based 
chemoimmunotherapy*
* Preliminary data from an ongoing phase II trial, 
10-H-0141. 12 CLL patients were treated with 
fludarabine and ofatumumab with or without 
cyclophosphamide for up to 4-6 cycles 
(unpublished).
Pre
Before treatment
p3C After 3 cycles of fludarabine-based 
chemoimmunotherapy.

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Amendment N, July 20, 2022
15
Figure 2. Absolute numbers and proportions of CD4+ and CD8+ T cells on a long-term follow up after 
fludarabine-based chemoimmunotherapy
      
* Preliminary data from an ongoing phase II trial, 
10-H-0141. 11 CLL patients were treated with 
fludarabine and ofatumumab with or without 
cyclophosphamide for up to 4-6 cycles 
(unpublished).
In this study, we will investigate the effect of the combination therapy on the depth of response and on the 
composition of the T-cell compartment. The depth of response is quantified by PB flow cytometry, which 
defines minimal residual disease (MRD) negativity as clonal B cells below detection frequency of 10-4 
cells/uL. MRD negativity will be used as a marker to guide treatment decisions on the long-term use of 
ibrutinib. T cell subsets are quantified and compared to the ongoing study using ibrutinib and short-course 
fludarabine (15-H-0172). 
2.8
Pembrolizumab
2.8.1
Mechanism of Action
The programmed cell death 1 (PD-1) pathway represents a major immune control switch, which may be 
engaged by tumor cells to overcome active T cell immune surveillance. The normal function of PD-1, 
expressed on the cell surface of activated T cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is a type I 
transmembrane glycoproteins. Upon engagement of its ligands, PD-L1 and PD-L2, the cytoplasmic tail of 
PD-1 recruits tyrosine phosphatases SHP-1 and SHP-2 to the immunoreceptor tyrosine-based switch motif 
(ITSM) motif, and dephosphorylates effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved 
in the CD3 T-cell signaling cascade. The ligands for PD-1 are constitutively expressed or can be induced in a 
variety of cell types. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found 
in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor. PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.

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Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
16
Pembrolizumab (KEYTRUDA®, MK-3475; previously known as SCH 900475 and ORG 307488-0 [herein 
referred to as pembrolizumab unless otherwise noted]) is a potent and highly selective humanized monoclonal 
antibody of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes 
to facilitate tumor regression and ultimately immune rejection. 
Pembrolizumab potentiates existing immune responses only in the presence of antigen-receptor stimulation 
and does not nonspecifically activate all T cells. Pembrolizumab was tested for its capacity to enhance T cell 
activity in vitro using blood cells from healthy volunteers stimulated with staphylococcus enterotoxin B 
(SEB). Pembrolizumab enhanced IL-2 production over control on average 2- to 4-fold at the highest antibody 
concentration tested (25 μg/mL). In addition to IL-2, levels of tumor necrosis factor alpha (TNFα), IL-17, IL-
6, and interferon gamma (IFNγ) increased by 1.2 to 1.7 folds after the addition of pembrolizumab to SEB-
stimulated whole blood cells.
2.8.2
Pharmacokinetics
Pembrolizumab potently blocks binding of PD-1 to both PD-L1 and PD-L2 with half maximal inhibitory 
concentration (IC50) values below 1 nM. Pembrolizumab enhances T-cell responses in human donor blood 
cell cultures, with a half-maximal effective concentration (EC50) of approximately 0.1 to 0.3 nM. 
The pharmacokinetics (PK) of pembrolizumab was studied in 479 patients who received doses of 1 to 10 
mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on a population PK analysis, the mean [% 
coefficient of variation (CV%)] clearance (CL) is 0.22 L/day (28%) and the mean (CV%) elimination half-life 
(t1/2) is 26 days (24%). Steady-state concentrations of pembrolizumab were reached by 18 weeks of repeated 
dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration 
(Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady 
state (AUCs) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 
weeks. 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to Investigator Brochure).  Pharmacodynamics data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK and 
pharmacodynamics data provides scientific rationale for monthly dosing schedule. 
An open-label phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical activity of 
single agent pembrolizumab. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 
mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors.  All three 
dose levels were well tolerated and no dose-limiting toxicities were observed.  This first in human study of 
MK-3475 showed evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date. Recent data from other 
clinical studies within the pembrolizumab program has shown that a lower dose of pembrolizumab and a less 
frequent schedule may be sufficient for target engagement and clinical activity. The differences in exposure 
for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma 
indication. The exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 
mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure).

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Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
17
2.8.3
Metabolism and Clearance
No traditional metabolism studies were conducted with pembrolizumab per current ICH S (R1) guidance on 
preclinical safety evaluation of biotechnology-derived pharmaceuticals. However, in vivo studies were 
conducted in C.B17 SCID mice to demonstrate the lack of Fab-arm or half molecule exchange for 
pembrolizumab. IgG4 wild type molecules can undergo in vitro and in vivo molecular rearrangement called 
Fab -arm (or half molecule) exchange by swapping their half molecule with other IgG4 half molecules, thereby 
generating bispecific or hybrid antibodies. A point mutation (S228P) in the core hinge region in IgG4 has been 
shown to be sufficient to prevent the Fab-arm exchange. The results supported that pembrolizumab, which has 
a hinge mutation from S to P at position 228, did not form detectable hybrid antibodies with co-administered 
wild type IgG4 molecules in vivo in SCID mice. This observation is consistent with the results of extensive in 
vitro characterization of pembrolizumab and indicates that pembrolizumab is not likely to engage in Fab-arm 
exchange in humans
Renal Impairment
The effect of renal impairment on the clearance (CL) of pembrolizumab was evaluated by population PK 
analyses in patients with mild (eGFR 60 to 89 mL/min/1.73 m2; n=210), moderate (eGFR 30 to 
59mL/min/1.73m2; n=43), or severe (eGFR 15 to 29mL/min/1.73 m2; n=2) renal impairment compared to 
patients with normal (eGFR greater than or equal to 90 mL/min/1.73m2; n=221) renal function. No clinically 
important differences in the CL of pembrolizumab were found between patients with renal impairment and 
patients with normal renal function. 
Hepatic Impairment
The effect of hepatic impairment on the CL of pembrolizumab was evaluated by population PK analyses in 
patients with mild hepatic impairment (total bilirubin (TB) less than or equal to upper limit of normal (ULN) 
and AST greater than ULN or TB between 1 and 1.5 times ULN and any AST; n=59) compared to patients with 
normal hepatic function (TB and AST less than or equal to ULN; n=410). No clinically important differences 
in the CL of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic 
function. Pembrolizumab has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN 
and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment.
2.8.4
Summary of clinical efficacy and safety
Clinical efficacy
Pembrolizumab demonstrated clinically meaningful benefit in the treatment of melanoma, non-small cell lung 
cancer (NSCLC), small cell lung cancer (SCLC), head and neck squamous cell carcinoma (HNSCC), classic 
Hodgkin lymphoma (cHL), primary mediastinal B cell lymphoma (PMBCL), urothelial cancer (UC), 
microsatellite instability-high (MSI-H) cancer, gastric or gastroesophageal junction (GEJ) adenocarcinoma, 
esophageal cancer, cervical cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), renal cell 
carcinoma (RCC), endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, cutaneous 
squamous cell carcinoma (cSCC), and MSI-H colorectal carcinoma (CRC). A dosing regimen of 400 mg 
pembrolizumab Q6W also demonstrated clinically meaningful benefit for all of the approved adult indications.
Clinical trials using pembrolizumab in other solid and hematologic malignancies are ongoing, including a phase 
1b/2 trial combining a BTK inhibitor and pembrolizumab in B cell malignancies (NCT02362035).
Monotherapy Safety Data

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Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
18
Pembrolizumab monotherapy has a positive benefit-risk profile and is well tolerated in the approved indications, 
as evidenced by a low rate of toxicity Grade 3 to 5 drug-related AEs (13.8%), discontinuations due to AEs 
(11.9%), and deaths due to drug-related AEs (0.4%) in the reference safety dataset (RSD). Furthermore, the 
frequency of immune-mediated AEs of special interest is low, and these events are readily managed in the 
clinical setting for guidance on management of immune and non-immune-mediated events of interest. Overall, 
the safety profile of pembrolizumab as defined by the RSD has remained generally consistent with accrual of 
additional data and participant exposure as represented by the cumulative running safety dataset (CRSD). 
Combination Therapy Safety Data
Safety data for pembrolizumab combination therapies were investigated in KN021, KN189, KN407, KN048, 
KN426, and KN146. In NSCLC and HNSCC, the safety profiles for pembrolizumab combination therapies 
were generally consistent with the known safety profiles of pembrolizumab monotherapy and the respective 
chemotherapy regimens administered (KN021, KN189, KN407, and KN048). In RCC, the safety profile of 
pembrolizumab in combination with axitinib was generally consistent with the established safety profile of 
pembrolizumab monotherapy in solid tumors and the observed safety profile for axitinib monotherapy, with the 
exception of increased incidences of Grades 3 and 4 elevated ALT and AST. ALT and AST elevations were 
generally manageable with interruption or discontinuation of pembrolizumab and axitinib, with or without 
concomitant steroid therapy (KN426). In endometrial carcinoma, the safety profile of pembrolizumab, when 
used in combination with lenvatinib, was generally consistent with the known safety profiles of each drug when 
used as monotherapy, with the exception of an increase in immune-related AEs largely comprised of low-grade 
hypothyroidism, with smaller increases in other immune-related AEs (KN146).
For more detailed information refer to the current version of the Investigator Brochure.
2.9
Ibrutinib
2.9.1
Pharmacokinetics and product metabolism
Following oral administration of ibrutinib at doses ranging of 420, 560, and 840 mg/day, exposure to ibrutinib 
increased as doses increased with substantial intersubject variability.  The mean half-life (t1/2) of ibrutinib across 
3 clinical studies ranged from 4 to 6 hours, with a median time to maximum plasma concentration (Tmax) of 1 
to 2 hours. Taking into account the approximate doubling in mean systemic exposure when dosed with food 
and the favorable safety profile, ibrutinib can be dosed with or without food. Ibrutinib is extensively 
metabolized primarily by cytochrome P450 (CYP) 3A4. The on-target effects of metabolite PCI-45227 are not 
considered clinically relevant. Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first 
dose exposure. About 8% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with 
creatinine clearance (CrCl) >30 mL/min. Patients with severe renal impairment or patients on dialysis have not 
been studied. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in 
subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) 
hepatic impairment compared to subjects with normal liver function.  A higher proportion of Grade 3 or higher 
adverse reactions were reported in patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic dysfunction 
compared to patients with normal hepatic function. 
For the most up to date and comprehensive pharmacokinetics (PK) and product metabolism information 
regarding ibrutinib, please refer to the current IB.

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Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
19
2.9.2
Summary of clinical safety
A brief summary of safety data from the monotherapy and combination therapy studies is provided below. For 
more comprehensive safety information please refer to the current version of the IB. Additional safety 
information is available for approved indications in prescribing labels in the United States.
For monotherapy studies:
Integrated safety data for a total of 1,600 patients with hematologic malignancies treated with ibrutinib 
monotherapy in 21 studies that have completed primary analysis or final analysis as of the 12 November 2020  
for the current IB.  Results are summarized below. The median duration of ibrutinib exposure for patients with 
hematologic malignancies receiving ibrutinib monotherapy was 15.3 months and the mean was 18.4 months. 
Treatment-emergent AEs (TEAEs) were reported in 98.8% of subjects. The most frequently reported TEAEs 
(> 20%) were diarrhea, fatigue, cough, nausea, upper respiratory tract infection, anemia, and pyrexia. Grade 3 
or 4 TEAEs were reported in 70.9% of subjects. The most commonly reported Grade 3 or 4 TEAEs (> 5%) 
were neutropenia, pneumonia, thrombocytopenia, anemia, and hypertension. 
Serious TEAEs were reported in 53.33% of subjects. The most frequently reported (> 2%) serious TEAEs were 
pneumonia, atrial fibrillation, pyrexia, febrile neutropenia, sepsis, and cellulitis. Fatal TEAEs (Grade 5) were 
reported in 9.9% of subjects during study treatment or within 30 days of discontinuation of treatment. The most 
frequently reported (>0.3%) fatal TEAEs (other than disease progression) were MCL, Richter’s syndrome, 
pneumonia, sepsis, respiratory failure, cardiac arrest, CLL, and death.
For combination therapy studies:  
Integrated safety data for a total of 1,971 subjects with hematologic malignancies treated with ibrutinib as 
combination therapy in 17 studies that have completed primary or final analysis on 12 November 2020 are 
summarized below. Various therapies were used in combination with ibrutinib in these studies: BR 
(bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and rituximab), ofatumumab, R-CHOP 
(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), cytarabine, azacitidine, 
dexamethasone, durvalumab, ofatumumab, lenalidomide with cyclophosphamide, EPOCH-R (doxorubicin, 
etoposide, vincristine, prednisone, rituximab), nivolumab, obinutuzumab, rituximab, carfilzomib with or 
without dexamethasone, pomalidomide plus dexamethasone, and bortezomib plus dexamethasone. The median 
duration of ibrutinib exposure for patients receiving ibrutinib as combination therapy was 9.2 months and the 
mean was 19.6 months. 
Treatment-emergent AEs were reported in 99.5% of subjects receiving ibrutinib as combination therapy. The 
most frequently reported hematologic TEAEs (>20%) were anemia, neutropenia, and thrombocytopenia. The 
most frequently reported nonhematologic TEAEs (>20%) were diarrhea, fatigue, nausea, pyrexia, cough, upper 
respiratory tract infection, and constipation. Treatment-emergent AEs that were considered by the investigator 
to be related to ibrutinib were reported in 89.1% of subjects. The most frequently reported (>10%) hematologic 
TEAEs related to ibrutinib were neutropenia, anemia,  thrombocytopenia, platelet count decreased, and 
neutrophil count decreased. The most frequently reported (>10%) nonhematologic TEAEs related to ibrutinib 
were diarrhea, fatigue, and nausea. Grade 3 or 4 TEAEs were reported in 82.9% of subjects. The most frequently 
reported (>5%) grade 3 or 4 hematologic TEAEs were neutropenia, anemia, neutrophil count decreased, 
thrombocytopenia, lymphocyte count increased, febrile neutropenia, and white blood cell count decreased. 
Pneumonia and hypertension were the most frequently reported non-hematologic Grade 3 or 4 TEAEs (>5%). 

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Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
20
Serious TEAEs were reported in 55.7% of subjects; the most frequently reported (> 2%) were pneumonia, 
febrile neutropenia, atrial fibrillation, pyrexia, and anemia. Fatal TEAEs were reported in 7.5% of subjects. The 
most frequently reported (>0.3%) fatal TEAEs (other than disease progression) were pneumonia, septic shock, 
death, and sepsis. 
Pneumonia was rarely, in less than 1% of cases, attributed to the infection of Pneumocystis jirovecii.  Most 
cases of Pneumocystis pneumonia (PCP) were reported from different monotherapy studies or combination 
studies. In Pharmacyclics’s analysis of cases of PCP in the Ibrutinib Clinical Trial Database and noted in the 
Ibrutinib Investigational Brochure, which utilized a broad search strategy, the rate of PCP (regardless of 
seriousness or relatedness) was <1%.
3.0
STUDY DESIGN 
This is a phase II, single-center, open-label study. The study has a single treatment arm using ibrutinib, short-
course fludarabine, and pembrolizumab in CLL or SLL patients with high-risk features defined by the protocol. 
Treatment plan is discussed in detail under section 5.0 Treatment Plan.
4.0
ELIGIBILITY ASSESSMENT AND ENROLLMENT
4.1
Inclusion Criteria
1.
Men and women with histologically confirmed CLL or SLL as defined by the following:

CLL: clonal B lymphocytosis ≥ 5,000 cells/L.

SLL: lymphadenopathy with the tissue morphology of CLL but are not leukemic (< 5,000 
circulating clonal B lymphocytes/L).

Immunophenotypic profile or immunohistochemistry read by an expert pathologist as consistent 
with CLL.  This will include CD5, CD19, and CD20 expression by the CLL cells typically also 
with CD23 expression, but CD23 negative cases may be included if there is an absence of t(11;14).
2.
 Active disease as defined by at least one of the following (IWCLL consensus criteria): 

Weight loss ≥10% within the previous 6 months. 

Extreme fatigue.

Fevers of greater than 100.5ºF for ≥2 weeks without evidence of infection.

Night sweats for more than one month without evidence of infection.

Evidence of progressive marrow failure as manifested by the development of, or worsening of, 
anemia and/or thrombocytopenia.

Massive or progressive splenomegaly.

Massive nodes or clusters or progressive lymphadenopathy.

Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated 
doubling time of less than 6 months.
3.
High-risk disease defined by meeting at least one of the following criteria:

Relapsed and/or refractory CLL/SLL. 

Presence of high-risk genetic changes detected by FISH, karyotype, sequencing or tissue 
expression, regardless of prior treatments status.
-
Deletion 17p
-
Complex cytogenetics (3 or more abnormalities)

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-
TP53 or NOTCH1 or SF3B1 mutation. Pathologic mutations occurring at the coding regions 
are accepted as relevant mutations. 
-
MYC aberration. Aberration includes rearrangement, amplification, and tissue expression by 
immunohistochemistry. 

CLL or SLL with disease transformation with Hodgkin-like cells regardless of prior treatment 
status.
4.
Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
5.
Adequate organ function as defined in Table 4.
Table 4. Summary of adequate organ function for eligibility
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥ 750/L
Platelets
≥ 50,000/L
Hemoglobin
≥ 9 g/dL or ≥ 5.6 mmol/L without EPO dependency (within 7 
days of assessment). Post-transfusion hemoglobin is accepted.
Renal
Measured or calculated GFR
GFR ≥ 30ml/min/1.73m2 based on CKD-EPI
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels ≥ 
1.5 ULN due to Gilbert's disease OR
Direct bilirubin may be > 1.5 x ULN if due to hemolytic anemia 
AND other labs relevant to hepatic function  (i.e. AST/ALT, Alk 
Phos) are within normal ranges
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN 
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
6.
Agreement to use acceptable methods of contraception during the study and for 90 days after the last 
dose of study drug if sexually active and able to bear or beget children.

Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses 
for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of 
bilateral oophorectomy). 

Female subjects of childbearing potential must have a negative serum pregnancy test upon study 
entry.

Male and female subjects who agree to use both a highly effective methods of birth control (i.e., 
implants, injectables, combined oral contraceptives, some intrauterine devices, complete abstinence, 
or sterilized partner) and a barrier method (i.e., condoms, vaginal ring, sponge, etc) during the period 
of therapy and for 90 days after the last dose of study drug
7.
Willing and able to participate in all required evaluations and procedures in this study protocol 
including swallowing capsules without difficulty.

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Amendment N, July 20, 2022
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8.
Ability to understand the purpose and risks of the study and provide signed and dated informed consent 
and authorization to use protected health information (in accordance with national and local subject 
privacy regulations).
9.
Individuals ≥ 18 years old
4.2
Exclusion Criteria

Transformation of CLL into lymphomas other than those with Hodgkin-like cells.

Currently receiving or previously participated to receive an investigational agent within 4 weeks prior 
to study treatment.

Currently receiving or previously received monoclonal antibodies, immunomodulatory therapy, 
chemotherapy, radiation, or radioimmunotherapy within 4 weeks prior to study treatment, or has not 
recovered (i.e., ≤ Grade 1 or at baseline) from non-hematologic adverse events due to a previously 
administered agent.
o Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to 
CTCAE, v4.03, grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria with 
the exception of alopecia.

Major surgery within 4 weeks of first dose of study drug
-
Note: If subject received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy. 

Currently receiving systemic steroid therapy (i.e. prednisone) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of trial treatment.

Prior therapy with BTK inhibitor, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
-
Note: Prior therapy with fludarabine is not excluded.

Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of 
disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 

Known additional malignancy that is progressing or requires active treatment. 
-
Note: Exceptions include basal cell carcinoma of skin, squamous cell carcinoma of skin, and in situ 
cervical cancer that has undergone potentially curative therapy. Exceptions include other cancers 
from which the subject has been disease-free for ≥ 2 years or which will not limit survival to < 2 
years

Known history of, or any evidence of active, non-infectious pneumonitis that required steroids.

Known bleeding disorders (i.e., von Willebrand’s disease or hemophilia).

Known HIV infection (i.e., HIV 1 and 2 antibodies).

Active hepatitis B (i.e., HBsAg reactive) or hepatitis C (i.e., HCV RNA is detected by a qualitative 
test) infection.   

Recent known active infection requiring systemic therapy that was completed ≤ 14 days before the first 
dose of study drug.

Known history of active tuberculosis.

Any uncontrolled active systemic infection.

Known hypersensitivity to ibrutinib, fludarabine, or pembrolizumab.

Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K antagonists.

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Amendment N, July 20, 2022
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
Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the 
stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction

History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug

Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first 
dose of ibrutinib or subjects who require continuous treatment with a strong CYP3A inhibitor 
(Appendix B). 

Currently active, clinically significant cardiovascular disease including uncontrolled or symptomatic 
arrhythmias, Class 3 or 4 congestive heart failure as defined by New York Heart Association Functional 
Classification, or a history of myocardial infarction, unstable angina or acute coronary syndrome within 
6 months of screening.

Life-threatening illness, medical condition or organ system dysfunction which, in the investigator's 
opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib 
and fludarabine, or put the study outcomes at undue risk

Female patients who are currently in pregnancy or unwilling to use acceptable methods of contraception 
or refrain from pregnancy if of childbearing potential or currently breastfeeding.  Male patients who 
are unwilling to follow the contraception requirements described in this protocol.

Psychiatric illness/social situations that would limit the patient’s ability to tolerate and/or comply with 
study requirements.

Unable to understand the investigational nature of the study or give informed consent.

Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the 
Child Pugh classification (Appendix C). 

Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
5.0
TREATMENT PLAN  
5.1
Drug administration and treatment schedule

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Amendment N, July 20, 2022
24
1) Conditioning phase (12 weeks): 
• Cycle -3 and -1 (28-day cycle ±5 days): ibrutinib 420mg PO daily
Ibrutinib is given 420mg (3 x 140mg) PO daily starting from cycle -3. Administration of ibrutinib will take 
place at the outpatient facility of the NIH clinical center or at the patient’s home. Each dose of ibrutinib is taken 
around the same time each day with a glass of water. The capsules should be swallowed intact and subjects 
should not attempt to open the capsule or dissolve them in water. There is one specific dietary restriction to 
avoid grapefruit juice and Seville oranges due to CYP450 3A4 inhibition. No dose adjustments are required for 
creatinine clearance.
• Cycle -2 (28-day cycle ±5 days): ibrutinib 420mg PO daily, fludarabine 25mg/m2/day IV on day 1-5 
Ibrutinib is continued 420mg PO daily during cycle -2. Fludarabine is given 25 mg/m2/day IV on days 1-5 of 
cycles -2. Fludarabine administration will take place in the Clinical Center Day Hospital. At the PI’s 
discretion, select subjects may be admitted to the inpatient unit for the first few days of fludarabine infusion. 
Subjects will have a peripheral line placed.  At the PI discretion, a central line may be placed in select 
patients. Dosing will be based on actual weight for all patients. No dose adjustment is required based on age. 
In the event of renal impairment, dose reduction will be as follows; 

Creatinine clearance of 30-70 mL/min/1.73m2 using the CKD-EPI equation with actual body weight: 
Fludarabine will be dose reduced by 20%. 

Creatinine clearance of ≤ 30 mL/min/1.73m2 using the CKD-EPI equation with actual body weight: 
Fludarabine will be held at the discretion of the PI.
2) Immunotherapy phase (1 year): 
• Cycle 1 to 17 (21-day cycle ±5 days): ibrutinib 420mg PO daily, pembrolizumab 200mg IV on D1 of each 
cycle
Ibrutinib is continued 420mg PO daily during the immunotherapy phase. Pembrolizumab is given as 200mg IV 
every 3 weeks from cycle 1 to 17 (or 1 year of immunotherapy phase, whichever is earlier). Pembrolizumab 
will be administered in the Clinical Center Day Hospital. At the PI’s discretion, select subjects may be admitted 
to the inpatient unit for the first pembrolizumab infusion. Subjects will have a peripheral line placed.  At the PI 
discretion, a central line may be placed in select patients. No dose adjustments are required for age or creatinine 
clearance.
3) Follow-up phase (indefinite): 
After 1 year of pembrolizumab, time on study equals chronological months from cycle 1 (when pembrolizumab 
is first given). At 2 years, all patients are evaluated for response and MRD status.  

All patients are followed up in 4-month intervals (±14 days) after 1 year of pembrolizumab.

Ibrutinib will be discontinued at the first follow up visit after 2 years in patients who achieve both CR 
and MRD negativity at 2 years. This is to allow sufficient turn-around time for flow cytometry results. 

For previously untreated patients who do not achieve both CR and MRD negativity at 2 years, ibrutinib 
will be continued as 420mg PO daily until progression or intolerable side effects occur. 

Relapsed/refractory patients will continue ibrutinib 420mg PO daily until progression or intolerable side 
effects occur regardless of response or MRD status at 2 years. 

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Amendment N, July 20, 2022
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5.2
Prophylactic medications  

Allopurinol (or alternative agent if the subject cannot tolerate allopurinol) during cycle -2 days 1-7 for all 
subjects, and beyond at the discretion of the PI.

Sulfamethoxazole/trimethoprim (or alternative agent in case of sulfa allergy) from cycle -3 to 4 (for 
approximately 6 months), and beyond at the discretion of the PI.

Acyclovir or valacyclovir at the discretion of the PI (not mandatory).
5.3
Dose modification guidelines for drug-related adverse events
An interruption of study drug administration is permissible. Dose changes must be recorded in the Dose 
Administration eCRF. 
5.3.1 Hematologic Toxicities
Dose modifications for hematologic toxicities have been updated to reflect recommended dose modifications 
from the May 2022 FDA label for ibrutinib.
Drug
Cycle
Condition at the 
start of cycle
Action*
Ibrutinib
3 and 
onwards
Grade >= 3 
neutropenia with 
infection or fever
OR
Grade >=3 
thrombocytopenia 
with bleeding
OR
Grade 4 
hematologic 
toxicities
Check CBC with differential weekly. 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline.

First occurrence: Resume ibrutinib at 280 mg once daily.

Second occurrence: Resume ibrutinib at 140 mg once daily. 
Third occurrence: discontinue ibrutinib.
Fludarabine
-2
HGB <11 g/dL 
with indications of 
autoimmune 
hemolysis
Omit fludarabine.
ANC <1,000/μL 
OR 
PLT <75,000/μL
Hold fludarabine for 4 weeks and check CBC with differential weekly.
Give fludarabine if ANC ≥1,000/μL AND PLT ≥75,000/μL. 
Cycle -2 can be extended in 4-week increments. Up to two dose delays 
are allowed (total 8 weeks).
If count recovery does not occur in 8 weeks, omit fludarabine.
Pembrolizumab
1 through 
17
ANC <750/μL, 
OR
HGB <9g/dL
OR
PLT <50,000/μL
Hold pembrolizumab for 3 weeks and check CBC with differential 
weekly. Reevaluate at the next cycle.
Give pembrolizumab if ANC ≥750/μL AND Hgb ≥9 g/dL AND PLT 
≥50,000/μL.
Up to three dose delays are allowed (total 9 weeks).
If count recovery does not occur in 9 weeks, omit pembrolizumab.
ANC - absolute neutrophil count; HGB - hemoglobin; PLT - platelet.
* Dose delay or reduction is not required if cytopenia is considered related to CLL.
5.3.2 
Cardiac Toxicities
Atrial fibrillation  

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Amendment N, July 20, 2022
26

For new-onset atrial fibrillation, ibrutinib will be held until cardiac evaluation has been completed. The 
decision to restart ibrutinib will be made after the PI and a consulting physician determine the subject 
is sufficiently stable following diagnostic testing and institution of treatment if required.

Anticoagulation with atrial fibrillation: If anticoagulation is deemed necessary by consulting physician 
and/or PI, patients will be allowed to start treatment with anti-platelet or anti-coagulant therapies except 
warfarin. Co-administration with warfarin has been associated with grade 3 or higher bleeding events 
such as (subdural hematoma, gastrointestinal bleeding, hematuria, and post procedural hemorrhage). 
Other forms of anti-platelet, anti-coagulant, direct thrombin inhibitors, or factor Xa inhibitors may be 
used concomitantly with ibrutinib, however the risk of increased bruising or bleeding is unknown. 
Patients will be counseled and monitored closely for signs of bleeding and/or bruising and will be 
instructed to contact the research team and primary care physician in the case of any complications.
Heart Failure
Dose modifications for heart failure have been updated to reflect recommended dose modifications 
from the May 2022 FDA label for ibrutinib.
Adverse Reaction
Occurrence
Action
1st
Hold ibrutinib until recovery to Grade ≤ 1 or baseline;  
restart at one  dose level lower (280 mg daily).
2nd
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; 
restart at one dose level lower (140 mg daily).
Grade 2 
Heart failure
3rd
Discontinue ibrutinib 
Grade 3 or 4
Heart failure
1st
Discontinue ibrutinib
Cardiac arrhythmias
Dose modifications for cardiac arrhythmias have been updated to reflect recommended dose 
modifications from the May 2022 FDA label for ibrutinib.
Adverse Reaction
Occurrence
Action
1st
Hold ibrutinib until recovery to Grade ≤ 1 or baseline;  
restart at one  dose level lower (280 mg daily).
Grade 3
Cardiac arrhythmias
2nd
Discontinue ibrutinib 
Grade 4
Cardiac arrrhythmias
1st
Discontinue ibrutinib
5.3.3
Hepatic impairment

Refer to Appendix C for Child-Pugh classification.

Ibrutinib is metabolized in the liver. In the population PK analysis (1,202 subjects), 179 subjects 
(14.9%) had mild hepatic impairment according to National Cancer Institute criteria and 12 subjects 
(1.0%) had moderate hepatic impairment. These subjects did not show a significantly higher ibrutinib 
exposure compared with subjects with normal hepatic function. Therefore, subjects with clinically 

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Amendment N, July 20, 2022
27
significant hepatic impairment at the time of screening (Child- Pugh class B or C) are excluded from 
study participation. 

Concomitant use of strong CYP inhibitors is not permitted in subjects with chronic hepatic 
impairment. In a hepatic impairment study, data showed an increase in ibrutinib exposure. For 
subjects with mild liver impairment (Child-Pugh class A), the recommended dose is 280mg daily. For 
subjects with moderate liver impairment (Child-Pugh class B), the recommended dose is 140mg 
daily. Monitor subjects for signs of ibrutinib toxicity and follow dose modification guidance as 
needed. It is not recommended to administer ibrutinib to subjects with severe hepatic impairment. 
Dose modification of ibrutinib for subjects who develop hepatic impairment on study is summarized 
as follows:
Table 6. Dose Modification Guidance for Hepatic Impaired Subjects
Child Pugh class A
(Mild hepatic impairment)*
Child Pugh Class B
(Moderate hepatic impairment)**
Child Pugh class C
(Severe hepatic 
impairment)
Ongoing at time 
of enrollment 
Develops 
during study 
Ongoing at time 
of enrollment 
Develops during 
study 
Develops during study 
Ibrutinib 
Dose 
(daily) 
280 mg 
280mg
140 mg
140 mg 
Hold until improves to 
moderate [Class B] or 
better)
* If further reduction is needed due to non-hepatic toxicity, dose may be reduced to 140 mg. In the event that 
additional reduction is needed, ibrutinib should be held for non-hepatic toxicity until resolution.
** If further reduction is needed due to non-hepatic toxicity, ibrutinib should be held until resolution. 

For subjects with existing chronic mild hepatic impairment (Child-Pugh class A) at enrollment, the 
starting dose has to be adjusted to a level of 280 mg daily (two capsules).

For subjects who develop mild liver impairment while on study (Child-Pugh class A), the 
recommended dose reduction for ibrutinib is to a level of 280 mg daily (two capsules). 

For subjects who develop moderate liver impairment while on study (Child-Pugh class B), the 
recommended dose reduction is to a level of 140 mg daily (one capsule). 

Subjects who develop severe hepatic impairment (Child-Pugh class C) must hold study drug until 
resolved to moderate impairment (Child-Pugh class B) or better. 

Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines in Section 5.4.4. 
5.3.4
Other non-hematologic toxicities
Ibrutinib

No dose adjustments are required for renal impairment.
   Hold ibrutinib for grade 3 or higher other non-hematologic toxicity associated with ibrutinib.  After  
resolution to grade ≤ 1 or baseline, ibrutinib will be restarted as follows:
Table 7. Guideline for holding ibrutinib related non-hematologic toxicities 

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Amendment N, July 20, 2022
28
Occurrence
Action
1st
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at one dose level lower 
(280mg daily).
2nd
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at one dose level lower 
(140mg daily).
3rd
Discontinue ibrutinib.

A high number of circulating malignant cells (>400,000/L) may confer increased risk; these subjects 
should be closely monitored. Administer supportive care such as hydration and/or leukapheresis as 
indicated. Ibrutinib may be temporarily held, and PI should be contacted. 

In the event that ibrutinib is held for toxicity for 28 consecutive days the study drug should be 
discontinued. However, if the PI deems that the clinical benefit outweighs the risk of restarting 
treatment then patient may restart study drug. 
Fludarabine

In the event of renal impairment, dose reduction will be done as specified in section 5.1.
   For grade 3 or higher other non-hematologic toxicities fludarabine can be interrupted and resumed when 
the toxicity resolves to grade 2 or lower. Fludarabine can be reinitiated at a full dose, 20% dose reduced, 
or completely stopped depending on clinical benefit-risk assessment by the PI. In select cases where a 
subject has uncomfortable grade 2 toxicities, dose may be interrupted or reduced per PI discretion.
Pembrolizumab

Adverse events (both non-serious and serious) associated with pembrolizumab exposure, including 
coadministration with additional compounds, may represent an immunologic etiology.  These adverse 
events may occur beginning shortly after the first dose or up to several months after the last dose of 
treatment. Pembrolizumab must be withheld or discontinued for drug-related toxicities and severe or 
life-threatening AEs as follows; 
Table 8: Dose Modification and Toxicity Management Guidelines for Immune-related AEs (irAEs) 
Associated with Pembrolizumab 
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
  Monitor participants for 
signs and symptoms of 

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Amendment N, July 20, 2022
29
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
followed by taper
  Add prophylactic antibiotics 
for opportunistic infections
pneumonitis
  Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment
Grade 2 or 3
Withhold
Diarrhea/Colitis 
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
  Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus)
  Participants with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and 
performing endoscopy to 
rule out colitis
  Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake 
is not feasible, fluid and 
electrolytes should be 
substituted via IV infusion
Grade 2 a
Withhold
  Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone or 
equivalent) followed by 
taper
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
  Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable)
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold d
  Initiate insulin replacement 
therapy for participants 
with T1DM
  Administer 
antihyperglycemic in 
participants with 
hyperglycemia
  Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes

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Amendment N, July 20, 2022
30
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
  Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Treat with nonselective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
  Monitor for signs and 
symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care
  Monitor for signs and 
symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by 
taper
  Monitor changes of renal 
function
Grade 2
Withhold
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes
Suspected SJS, 
TEN, or 
DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or 
DRESS
Permanently 
discontinue
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation 
to confirm etiology or 
exclude other causes
Persistent Grade 2 Withhold
Grade 3
Withhold or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
  Based on severity of AE 
administer corticosteroids
  Ensure adequate evaluation 
to confirm etiology or 
exclude other causes

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AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; 
ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal 
Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if 
baseline normal; >3.0 to 10.0 x baseline if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If 
control achieved or ≤ Grade 2, pembrolizumab may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs.
5.4
Holding of study drug administration
5.4.1
Ibrutinib and surgical procedures

Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery
depending upon the type of surgery and the risk of bleeding.
5.4.2
Medically necessary conditions to hold study drugs

Ibrutinib can be held at the study team’s discretion  for medically necessary conditions (i.e. concurrent 
infection, impending workups for diagnostic and/or therapeutic purposes)

Fludarabine or pembrolizumab infusions may be held for medically necessary reasons (i.e. concurrent 
infection, emergency of autoimmune cytopenia, impending workups for diagnostic and/or therapeutic 
purposes) and can be delayed up to 2 cycles while continuing ibrutinib until the medical reasons to hold 
infusion resolve or return to baseline. If the delay persists past 2 cycles, fludarabine will be omitted and 
the patient will continue treatment with ibrutinib. If pembrolizumab is delayed beyond 2 cycles, 
pembrolizumab can still be given after medical reasons to hold infusion resolve or return to baseline. 
Per PI discretion, patients may be given catch-up doses of pembrolizumab after cycle 17 to compensate 
for the missed doses as long as the medical reasons to hold the infusion have resolved or returned to 
baseline. Treatment should not be restarted in situations where the patient had been removed from 
therapy related to an adverse event that requires permanent discontinuation of pembrolizumab as 
described in Table 8.

Supportive medications including allopurinol and acyclovir (if indicated) will not be started until 
fludarabine starts and will not be initiated if fludarabine is omitted. Weekly CBC intended for cycle -2 
will be delayed until fludarabine starts and not performed if fludarabine is omitted.
5.4.3
Permanent discontinuation of study drug administration in case of treatment related adverse 
events 

Serious or life threatening cardiac arrhythmias 

Severe infection (requiring vasopressor support > 24h, or intubation) 

Any grade 4 toxicity excluding readily reversible metabolic or laboratory abnormalities or hematologic 
toxicities 

Progressive disease as defined in section 7.0

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
Pregnancy or unwillingness to use acceptable method of contraception

Other toxicities requiring permanent discontinuation of study drugs are defined in section 5.4.4. Non-
hematologic toxicities. 
Patients who are not able to receive further study drug administration will be followed  after resolution 
of the event for safety and will continue to be followed at regular intervals with reassessment of disease 
as outlined in section 6 and 7.
5.5
Supportive care (non-investigational)

Patients will be transfused packed red blood cells (must be irradiated) and/or platelets (must be 
processed using the Intercept Blood system) as clinically indicated.  

Filgrastim or peg-filgrastim may be used to if ANC < 500/uL at the PI’s discretion. 

Anti-infective agents will be used as indicated for treatment of intercurrent infections.

Prophylactic medications will be used as defined in section 5.3. Prophylactic medications. 
5.6
Permitted and non-permitted concomitant medications 

Patients may continue most medications they were prescribed prior to study enrollment for co-morbid 
conditions. No formal drug-drug interaction studies have been conducted therefore we ask patients to 
report all medications and over the counter drugs they are taking so we can monitor for any drug-drug 
interactions. Treatment for autoimmune cytopenias is permitted during cycles with ibrutinib alone 
(during cycle -3 and -1, and after cycle 17). Treatment for autoimmune cytopenias should not exceed 
14 days at doses that do not exceed 100mg per day of prednisone or equivalent. 
5.6.1  Guideline for the use of CYP3A inhibitors/inducers
Dose reduction of ibrutinib will be guided by ibrutinib USPI as follows.
Patient Population
Coadministered Drug
Recommended ibrutinib dose
B-cell Malignancies

Moderate CYP3A inhibitor
280 mg once daily 

Voriconazole 200 mg twice daily 

Posaconazole suspension 100 mg once daily, 
100 mg twice daily, or 200 mg twice daily 
140 mg once daily 

Posaconazole suspension 200 mg three times 
daily or 400 mg twice daily

Posaconazole IV injection 300 mg once daily

Posaconazole delayed-release tablets 300 mg 
once daily 
70 mg once daily
Other strong CYP3A inhibitors 
Avoid concomitant use. 
If these inhibitors will be used short-
term (such as anti-infectives for seven 
days or less), interrupt ibrutinib

After discontinuation of a CYP3A inhibitor, resume the previous dose of ibrutinib.

A list of common CYP3A inhibitors and inducers is provided in Appendix B. For further information, 
please refer to the current version of the Investigator Brochure. Examples  of inhibitors, inducers, and 
substrates may be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is 
continually revised and should be checked frequently for updates.

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33

For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please refer 
to the current version of the Investigator Brochure.
5.6.2 
Concomitant use of QT prolonging agents
Any medications known to cause QT prolongation should be used with caution; periodic ECG and electrolyte 
monitoring should be considered. 
5.6.3 
Concomitant use of antiplatelet agents and anticoagulants
Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet function. In 
an in vitro platelet function study, inhibitory effects of ibrutinib on collagen induced platelet aggregation were 
observed. Supplements such as fish oil and vitamin E preparations should be avoided during treatment with 
ibrutinib. Bleeding events of any grade, including bruising and petechiae, occurred in subjects treated with 
ibrutinib. Subjects with congenital bleeding diathesis have not been studied. Subjects requiring the initiation of 
therapeutic anticoagulation therapy (eg, atrial fibrillation) should be observed closely for signs and symptoms 
of bleeding and the risks and benefits of continuing ibrutinib treatment should be considered.  
5.6.4 
Concomitant use of systemic glucocorticoids
Systemic glucocorticoids should not be administered other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology or autoimmune cytopenia related to CLL.  The use of physiologic 
doses of corticosteroids may be approved per PI decision.
5.6.5 
Prohibited concomitant medications

Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy not specified in 
this protocol is prohibited while the subject is receiving treatment on study. 

For patients who were newly diagnosed with a second malignancy, the study drug can be interrupted 
while the patient undergoes further evaluation and treatment with definitive, time-limited anti-cancer 
therapy (i.e. localized breast cancer requiring surgery and adjuvant chemoradiation). If the second 
malignancy requires long-term therapy (> 6 months) or a definite therapy is not available (i.e. metastatic 
solid tumor), the patient will be taken off study.
5.7
Special instructions
5.7.1
Immunizations:  Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial are contraindicated. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid 
vaccine. Patients will be advised not to receive live viral vaccines . Subjects who would like to receive 
other routine non-attenuated vaccinations will be allowed to do so. The ability to generate an immune 
response to any vaccine following administration of ibrutinib has not been studied.
5.7.2
Birth control: Subjects with reproductive potential who are sexually active must use acceptable 
methods of contraception during the study and for 90 days after the last dose of ibrutinib.  Examples of 
acceptable methods of contraception include condoms, implants, injectables, combined oral 
contraceptives, intrauterine devices, true sexual abstinence, or sterilized partner.  Note  that periodic 
abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation methods or withdrawal, are not 
acceptable methods of contraception.

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34
5.7.3
Guidelines for rescue medications and supportive care
Subjects should receive appropriate supportive care measures as deemed necessary by the treating investigator.  
Suggested supportive care measures for the management of adverse events with potential immunologic etiology 
are outlined below. Where appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with administration 
of corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator is instructed to follow the 
ECI reporting guidance but does not need to follow the treatment guidance. Refer to Section 5.3 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography 
as part of evaluation of the event. Suggested conditional procedures, as appropriate, can be found in the ECI 
guidance document.
5.7.4
Immune-Infusion reactions
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely 
within 24 hours of completion of infusion. Table below shows treatment guidelines for subjects who experience 
an infusion reaction associated with administration of pembrolizumab.
Table 9. Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion 
rate (e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).

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35
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
be permanently discontinued from 
further trial treatment administration.
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued 
from further trial treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration.
6.0
CLINICAL MONITORING (see Appendix A. Schedule of Events) 
Samples will be ordered and tracked through the CRIS screens. Should a CRIS screen not be available, the NIH 
form 2803-1 will be completed and will accompany the specimen and be filed in the medical record. 
6.1
Study Evaluations: Screening and Baseline 
Results from other NIH protocols may be used as a part of the study evaluation. Selected results (viral studies, 
flow cytometry, CT, FISH and karyotype) performed from outside institutions will be accepted.
Screening/Baseline: Tests will be performed from day -28 to day 0 of starting study drug, unless otherwise 
specified. 

Complete medical history: relevant past medical history includes medical diagnoses and/or conditions; 
1) that are currently ongoing, OR 2) occurred within 1 year of study enrollment, OR 3) occurred before 
1 year of study enrollment and were potentially associated with major organ function or with long-term 
sequelae (i.e. hypertension, hyperlipidemia, diabetes, surgery of major organ system, any malignancy).

ECOG performance status (PS) evaluation

Physical exam will be performed and subjects will be monitored clinically for atrial fibrillation

Concomitant medication review

HLA typing, saliva (HLA typing performed at any timepoint, not limited to day -28 to day 0, is 
accepted)

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
Complete blood count (CBC) with differential 

Acute care & mineral panels (includes Na, K, Cl, CO2, creatinine, glucose, BUN, phosphorus, 
magnesium, albumin, and calcium)

Total protein, CK, Uric Acid, and LDH 

Hepatic panel (includes alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)

Reticulocyte count

PT, PTT

Serum protein electrophoresis with immunofixation (SPEP)

Serum free light chains, quantitative immunoglobulins 

C-reactive protein (CRP)

Beta-2 microglobulin (B2M)

Haptoglobin, direct antiglobulin test (DAT)

Iron panel (includes ferritin, transferrin, iron), folate, vitamin B12

Thyroid function panel (thyroid stimulating hormone, free T4, T3)

Viral studies (serologies for HIV 1 / 2, hepatitis B and C; HBV DNA PCR). Outside results are 
accepted.

For females of childbearing potential, one negative pregnancy tests sensitive to 50 mIU within 2 weeks 
prior to starting study drug.

Lymphocyte phenotyping (T, B, NK) 

IGHV mutation analysis (as this test does not change with time, any prior report is acceptable). Outside 
results are acceptable.

PB interphase FISH within 3 months prior to starting study drug. FISH panel contains probes for ATM 
(11q22.3), D12Z3 (12 cen), D13S319 (13q14.3), LAMP1 (13q34) and TP53 (17p13.1). Outside results 
are acceptable.

Karyotype within 3 months prior to starting study drug. Outside results are acceptable.

PB or BM chromosome tests (metaphase karyotype). This is an optional test.

Flow cytometry panel for CLL (may be done on blood, BM and/or LN) or immunohistochemistry of 
LN or BM demonstrating CLL/SLL within 3 months prior to starting study drug

CT of the neck, chest, abdomen and pelvis within 3 months prior to starting study drug.  IV and PO 
contrast will be used unless the patient has a contrast allergy or impaired renal function. Outside results 
are accepted.

BM aspirate and biopsy within 3 months of starting treatment. Outside results are accepted. 

EKG within 3 months prior to starting study drug

Lymphapheresis for research (optional)

LN biopsy for research if the patient is willing and has an accessible LN. Outside results are accepted.

Research blood (up to 80mL)
 Pre Cycle -3  (day -5 to day 0): If pre-cycle -3 visit overlaps with screening/baseline visit, selected 
evaluations will be performed (marked with * below). Other evaluations are optional.
Informed consent*
Interval medical history
ECOG PS
Physical exam
Concomitant medication review

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Amendment N, July 20, 2022
37
CBC with differential*
Acute care & mineral panels (includes Na, K, Cl, CO2, creatinine, glucose, BUN, phosphorus, 
magnesium, albumin, and calcium)*
Total protein, CK, Uric Acid, and LDH 
Hepatic panel (includes alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
Reticulocyte count
PT, PTT
B2M
Haptoglobin, DAT
Pregnancy test for females of childbearing potential
Research blood (up to  80ml)
6.2
On therapy evaluations
Cycle -2 until 1 year of pembrolizumab: before starting each cycle (+/- 5-day window):
Following assessments will be performed prior to each cycle. 

Interval History

ECOG PS

Physical exam

Concomitant medication review 

CBC with differential

Acute care & mineral panels (includes Na, K, Cl, CO2, creatinine, glucose, BUN, phosphorus, 
magnesium, albumin, and calcium)

Total protein, CK, Uric Acid, and LDH 

Hepatic panel (includes alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)

Thyroid function panel (thyroid stimulating hormone, free T4, T3) from Cycle 1 until 1 year

Reticulocyte count

PT, PTT

B2M

Haptoglobin, DAT

Pregnancy test for females of childbearing potential

Research blood (up to 80ml). Research blood is required for cycles -2, -1, and 1. Research blood is 
optional for other cycles. If dose delay of fludarabine or pembrolizumab occurs, research blood does 
not have to be repeated on subsequent visits intended for delayed therapy.
After 1 year of pembrolizumab (+/- 14-day window):
Following assessments will be performed every 4 months while on therapy until disease progression or 
intolerable side effects. Patients with travel hardships can be followed every 8 months and draw an interim 
CBC with differential to substitute a missed visit and evaluations. Outside lab results are accepted for the 
interim lab.

Interval History

ECOG performance status evaluation 

Physical exam

Concomitant medication review 

CBC with differential

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
Acute care & mineral panels (includes Na, K, Cl, CO2, creatinine, glucose, BUN, phosphorus, 
magnesium, albumin, and calcium)

Total protein, CK, Uric Acid, and LDH 

Hepatic panel (includes alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)

Reticulocyte count

PT, PTT

B2M

Haptoglobin, DAT

Thyroid function panel (thyroid stimulating hormone, free T4, T3; optional)

Pregnancy test for females of childbearing potential

Research blood (up to 80ml, optional)
Additional tests
Cycle -2  

Cycle -2 Day 14, and 22 (+/- 7 days): CBC with differential (may be performed outside). If fludarabine 
is delayed, these tests are also delayed until fludarabine is given. If fludarabine is omitted, interim labs will 
not be collected.
Cycle 1

Prior to cycle 1 (within 14 days prior to starting pembrolizumab): CT of the neck, chest, abdomen and 
pelvis.  IV and PO contrast will be used unless the patient has a contrast allergy or impaired renal function. 
Participants may waive the CT scan prior to pembrolizumab.
Others

Up to 3 lymph node biopsies may be obtained for research at any time during therapy (optional, with 
at least 4 weeks between biopsies).
6.3
Response assessment 
Response assessment will be performed after 6 months, 12 months, and annually thereafter (starting from 
cycle 1) (+/- 30-day window). Patients with travel hardships can defer assessments to subsequent clinic 
visits.

Interval History

ECOG performance status evaluation 

Physical exam

Concomitant medication review 

CBC with differential

Acute care & mineral panels (includes Na, K, Cl, CO2, creatinine, glucose, BUN, phosphorus, 
magnesium, albumin, and calcium)

Total protein, CK, Uric Acid, and LDH 

Hepatic panel (includes alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)

Reticulocyte count

PT, PTT

Serum free light chains, quantitative immunoglobulins 

CRP (optional)

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
B2M

Haptoglobin, DAT

Pregnancy test for females of childbearing potential

Lymphocyte phenotyping (T, B, NK) 

Flow cytometry panel for CLL optional (may be done on blood, BM and/or LN)

CT of the neck, chest, abdomen and pelvis (optional at 6 months, required at 12 months, and optional 
annually thereafter.) IV and PO contrast is optional and may be used unless the patient has a contrast 
allergy or impaired renal function. 

BM aspirate and biopsy is optional after 6 months on pembrolizumab, required at 12 months, and 
optional thereafter.

Lymphapheresis for research (optional)

Lymph node biopsy is optional and may be performed if the patient is willing and has an accessible 
lymph node.  

Research blood (up to 80ml) is optional past the primary endpoint.
6.4
At progression evaluation 
All response assessments as listed in section 6.3 Response assessment can be performed at progression if the 
patient remains available for the study (optional). Additional studies may be performed per the PI’s decision.
7.0
CRITERIA FOR RESPONSE
Responses for spleen and lymphadenopathy will be assessed using CT scans. In the absence of a CT scan 
assessment by physical exam may be substituted. Response assessments will be made by IWCLL 2008 
guidelines13 incorporating the 2012 and 2013 clarifications for patients treated with kinase inhibitors.74 
Response includes complete response, partial response, and partial response with lymphocytosis (Table below). 
Table 10. Criteria of response
Response
CR
PRF
PRLF
PDG
Group A
LymphadenopathyA
None >1.5cm
Decrease ≥ 50%
Decrease ≥ 50%
Increase ≥ 50% or 
any new lesion > 
1.5cm
Splenomegaly/ 
HepatomegalyB
None
Decrease ≥ 50%
Decrease ≥ 50%
Increase ≥ 50% or 
any new 
splenomegaly
Blood 
lymphocytesBC
< 4000/μL
Decrease ≥ 50% 
from baseline
Increase or <50% 
decrease over 
baseline
Increase ≥ 50% over 
baseline or > 
5000/μL
Bone marrowD
Normocellular, 
<30% lymphocytes, 
no B-lymphoid 
nodules 
Not applicable
Not applicable
Not applicable
Group BE
Platelet count
>100,000/μL
> 100,000/μL or 
increase ≥ 50% 
over baseline
> 100,000/μL or 
increase ≥ 50% over 
baseline
Decrease ≥ 50% 
from baseline 
secondary to CLL

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Hemoglobin
> 11.0g/dL
> 11.0 g/dL or 
increase ≥ 50% 
over baseline
> 11.0 g/dL or 
increase ≥ 50% over 
baseline
Decrease ≥ 50% 
from baseline 
secondary to CLL
Neutrophils
> 1500/μL
> 1500/μL or 
increase ≥ 50% 
over baseline
Not applicable
Not applicable
CR = complete response; CRi = CR with incomplete blood count recovery; CT = computed tomography; PD = progressive
disease; PR = partial response; PRL = partial response with lymphocytosis
Footnotes
A Sum of the product (SPDs) of up to 6 lymph nodes as evaluated by CT scans. If CT is unavailable, the absence of enlarged 
lymph nodes (> 1.5cm) documented by physical exam is acceptable. 
B Splenomegaly assessed by CT scan. In the absence of a CT scan assessment by physical exam may be substituted. New
splenomegaly or hepatomegaly is assessed by physical exam.
CPatients with treatment-related lymphocytosis remain on study unless associated with other signs of progressive disease. 
Treatment-related lymphocytosis may occur at the start of treatment or at any time when resuming treatment after a dose
interruption.
DComplete response requires confirmation with bone marrow biopsy. In the absence of a confirmatory bone marrow biopsy 
the response can be classified as CRu. In case of a hypocellular marrow the response can be classified as CRi.
E PR or PRL, at least one Group B criterion has to be met. CR, all criteria in A and B must be met. In subjects meeting 
Group A criteria for CR but not Group B, the response can be classified as CRi.
F PR and PRL criteria refer to changes from baseline.
G PD criteria refer to changes from baseline in subjects who never responded and to changes from best response (nadir) in 
subjects who responded.
Complete Response (CR)
• Is defined as meeting all criteria in A and B.
• Meet all criteria in A and B but bone marrow confirmation is pending: unconfirmed complete response (CRu).
• Meet all criteria in A but bone marrow is hypocellular, or criteria in B are not met: complete response with incomplete 
blood count recovery (CRi).
Partial Response (PR)
• Is defined by 2 criteria in Group A if abnormal before therapy and at least 1 Group B criterion.
• In subjects with just 1 involved Group A site (e.g., lymphadenopathy in a subject with SLL), the response is PR when 
the criterion for that site is met.
• If criteria for PR, except for a decrease in the number of blood lymphocytes by 50% or more from the value before 
therapy, are met, then assessment will be PRL.
• SLL subjects need to have both ALC >50% and ALC >5k to be PRL.
Progressive Disease (PD)
Progressive disease is defined by:
• Progressive lymphocytosis ≥50% from nadir, confirmed due to expansion of CLL cells by flow cytometry (≥5,000 B 
lymphocytes/µL).
• or an increase ≥50% in the sum of the products of at least two lymph nodes with at least one lymph node >1.5 cm in 
greatest diameter,
• or the appearance of a new pathologic lymph node >1.5 cm in greatest diameter,
• or new onset splenomegaly or hepatomegaly on physical exam, or other new CLL organ infiltrates,
• or an increase ≥50% in splenomegaly or hepatomegaly when occurring in the absence of a confounding process (e.g., 
infection), and that is maintained or continues to progress over a period of at least 3 months.

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Other criteria for PD include:
• Transformation to a more aggressive histology (e.g., Richter syndrome). Whenever possible, this diagnosis should be 
established by lymph node biopsy.
• The progression or development of cytopenia (excluding autoimmune cytopenia), as documented by a decrease of 
hemoglobin levels by >2 g/dL, or by a decrease of platelet counts by >50%, that persists for at least 3 months defines 
disease progression if a marrow biopsy supports a disease related etiology.
A rise of the lymphocyte count at the beginning of therapy or resumption of therapy after a period of drug hold in absence 
of other indications of progressive disease will not be considered as evidence of progressive disease because this type of 
agent does typically lead to a mobilization of tumor cells into the peripheral blood.
Transient increases of lymph node size during treatment with novel inhibitors may occur and should not be counted as 
progression.
8.0
ANCILLARY LABORATORY RESEARCH STUDIES
8.1
Collection of samples 

Blood samples: A volume not to exceed 550 ml of peripheral blood will be requested during the initial 
8-week period.  Subsequent research blood draws will typically consist of <100 ml of peripheral blood 
at follow up visits (not to exceed 550 mL in any 8-week period).

Lymphapheresis: Lymphapheresis may be performed in consenting subjects. 

BM samples: BM biopsy cylinder and up to 10cc of BM aspirate may be obtained for research at the 
time of the BM biopsy as indicated in Section 6.0. 

LN samples: LN biopsies may be obtained in consenting subjects. During the course of participating 
on this study, an additional 10 cc of blood (NIH visits only) and 5 cc of bone marrow aspirate each time 
a patient has a bone marrow examination may be requested. 

Saliva samples: Saliva samples may be collected anytime on study.
8.2
Intended use
These samples will be used for to explore the biologic effects on B- and T-cell subsets and function, we will;

Enumerate T (CD4, CD8), B, and NK cells in circulation 

Characterize T-cell subsets, including T-regulatory cells, Th-1, Th-2, Th-17

Characterize T-cell activation state and differentiation

Assess expression of checkpoint inhibitory molecules, including PD-L1 and PD-1

Genomic profiling of the B- and T-cell repertoire by CDR3 analysis

Measure pertinent cytokine and chemokine levels

Genomic testing for somatic mutations in the CLL clone
These specimens will not be used for diagnostic purposes. Leftover and additional samples may be used for the 
descriptive or exploratory ancillary research studies, and if done, may be correlated with the presence or absence 
of response. 
8.3
Genomic analysis
The scope of genomic analysis

Targeted sequencing of candidate genes 

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
Gene expression profiling

Genomic profiling of immune cell repertoire

Whole genome/exome sequencing

Sequencing cell-free DNA
Research grade genomic sequencing will be performed on banked samples to evaluate for somatic mutations 
possibly involved in the etiology and pathophysiology of blood diseases. Somatic mutation data will be obtained 
by subtracting germline sequencing data (saliva samples) from tumor sequencing data (blood, BM, LN 
samples). Banked samples collected serially from subjects enrolled on this protocol and subsequent treatment 
protocols may be analyzed at NHLBI, NIH, or external facilities, which will be specified to the IRB. 
Protection of privacy and confidentiality of biological specimen

Each sample is assigned a unique number. Vials holding patient samples are labeled with the 
sequential laboratory accession ID number that does not contain any protected health information 
(PHI). An electronic database is used to store patient information related to the coded samples. The 
laboratory is located in a controlled access building and laboratory doors are kept locked. Visitors to 
the laboratory are required to be accompanied by laboratory staff at all times.  Hard copy records or 
electronic copies of documents containing patient information are kept in the locked laboratory or 
other controlled access locations. 

Pedigrees will not be published.

Personally identifiable information will not be released to third parties. 

Clinical data (i.e. demographics and clinical outcome) and samples may be shared with other 
researchers once a research agreement is established and the amended protocol specifying the 
collaboration is approved by the IRB.

Genomic data will be deposited in a genomic database prior to publication.
Secondary findings
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable findings 
for the purpose of this study are defined as disorders appearing in the American College of Medical Genetics 
and Genomics (ACMG) recommendations for the return of incidental findings that is current at the time of 
primary analysis. Secondary (incidental) findings analysis will be performed by the NHGRI-NIHCC Secondary 
Genomic Findings Service (SGFS) team under its CLIA license. 
The SGFS process will evaluate exomes/genomes for secondary findings for each submitted exome or genome 
file. The PI will submit periodic datasets to the SGFS, comprising either full exome files, exome or genome 
variant files that encompass only the coding regions of the then current genes for which the SGFS provides 
analysis (e.g., the ACMG 59 gene list). These files will be configured per the specification of the NHGRI 
Bioinformatics Core and each file will include a coded individual identifier (no personally identifiable 
information) for which the PI retains the key.
If there is a secondary variant identified, the PI will be notified and should discuss the approach for validating 
this variant with the SGFS. Currently, the 2014 estimated yield is that 2 to 3% of participant will have such 
relevant findings. The SGFS will contact the PI to inform them of the finding and the PI will provide the PII 
(Name and contact information) of the individual with the finding.
The research participant will be contacted by either the primary team or the SGFS team to inform them that a 
secondary finding may be present, that it is potentially highly medically actionable, and that it is strongly 

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recommended that the participant submit a follow up sample (typically Oragene saliva DNA kit) to allow 
confirmation and clinical validation of this finding. The nature of the disease and the putatively mutated gene 
will not be disclosed in this call. If the participant presses, it may be disclosed that most of the findings relate 
to either heart disease or cancer susceptibility for which there are effective interventions to reduce pathogenic 
risk. If the participant agrees, the primary team will register the participant in CRIS (if not already registered) 
and enter a CRIS order for “Secondary Genomic Finding Confirmation Testing”. The SGFS will then send an 
Oragene collection kit to the participant. Upon return of the sample, the SGFS will perform CLIA-valid Sanger 
PCR testing for the variant and a clinical report will be generated that either confirms or refutes the research 
finding. If positive, the NHGRI consult attending and genetic counselor will review the variant, meet with the 
participant to disclose the finding, provide medical and genetic counseling for that variant, provide referrals for 
further evaluation/follow-up for the proband and give recommendations for testing for his/her family members. 
If the participant declines traveling to the NIHCC for this result, it will be returned by telephone. The clinical 
testing report will be uploaded into CRIS. Individual negative secondary findings analysis reports will not be 
returned to the participant or PI. Instead, the service will return a list of all exomes/genomes that were analyzed 
to the PI and an indication of which (if any) were positive.
8.4
Storage, tracking and disposition of samples and data
Storage: All samples will be coded and stored in the laboratory of Dr. Wiestner. Collected samples will be de-
identified prior to storage following current NHLBI DIR BSI Policy. Efforts to ensure protection of patient 
information as described in Section 8.3. 
Tracking:  Samples will be ordered and tracked through the CRIS Research Screens.  Should a CRIS screen 
not be available, the NIH form 2803-1 will be completed and will accompany the specimen and be filed in the 
medical record.  Samples will not be sent outside NIH without IRB notification and an executed MTA or CTA. 
De-identified human serum and/or plasma and/or tumor samples and clinical data from patients with B-cell 
malignancies may be sent to Dr. Dan Landau, Weill Cornell Medical College.
End of study procedures:  Samples from consenting subjects will be stored until they are no longer of scientific 
value or if a subject withdraws consent for their continued use, at which time they will be destroyed. 
Loss or destruction of samples: Should we become aware that a major breech in our plan for tracking and 
storage of samples has occurred, the IRB will be notified.
9.0
BIOSTATISTICAL CONSIDERATIONS
9.1
Primary endpoint
To test the efficacy (CR at 12 months) and safety of combination of ibrutinib, fludarabine, and pembrolizumab 
in patients with high-risk and/or relapsed/refractory chronic lymphocytic leukemia (CLL) and small 
lymphocytic leukemia (SLL), primary endpoint is defined as the rate of complete response (CR) after 12 months 
from cycle 1. Response to treatment will be determined according to IWCLL 2008 criteria incorporating 2012 
and 2013 clarifications pertaining to patients treated with kinase inhibitors. 
9.2
Secondary endpoints

Tolerability to the combination regimen

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
Overall response rate (ORR) 

Best response

Duration of response (DOR)

Progression-free survival (PFS)

Overall survival (OS)

Minimal residual disease (MRD) status defined by flow cytometry 

Shifts in cellular and humoral immunity on treatment (i.e., B- and T-cell counts and repertoire)

Expression of checkpoint inhibitory molecules (i.e., PD-L1 and PD-1)
9.3
Sample size 
The study will enroll 25 evaluable subjects for response assessment for primary endpoint.  Up to 5 additional 
subjects may be enrolled to account for early discontinuation before completing 1-year on treatment due to non-
treatment related reasons. Subjects who discontinue study treatment early due to non-treatment related reasons 
are not included in the evaluation of the primary endpoint.   
For the primary endpoint, CR with ibrutinib alone has been reported to be 4-13% in a previously untreated CLL 
population,47,60 and 0-2% in relapsed/refractory CLL.45,46 When ibrutinib and rituximab were combined in high-
risk CLL patients, CR rate was 8%.49 Based on the reported data, a CR rate exceeding 30% would generate an 
interest for further studies.  We will test the null hypothesis (H0) that the CR rate in the study is ≤10% against 
alternative hypothesis (H1) that CR is >10% with type I error of 0.05.  A sample size of 25 evaluable patients 
will have 81% power to detect a 20% difference based on a one-sided binominal test. The null hypothesis is 
rejected if 6 or more CRs are observed in 25 subjects.  
Early discontinuation within the first year due to toxicity related to the study drugs is counted as non-response 
towards the primary endpoint. 
9.4
Statistical Methods
The planned analyses will include descriptive statistics on the proportions of overall response. The response 
probabilities will be estimated using the sample proportions and their inferences including confidence intervals 
and hypotheses testing will be evaluated using Binomial distributions. Time to response, overall survival and 
the PFS time will be analyzed using appropriate nonparametric tools in survival analysis such as Kaplan-Meier 
estimates taking consideration of random censoring.  
In addition, methods based on survival analysis, cumulative incidence rates and other competing risk models 
will be used to evaluate the treatment effects.  Graphical tools will be used to display the appropriate estimates 
(i.e. estimated proportions and Kaplan-Meier curves) and their corresponding 95% confidence intervals. 
9.5
Study Stopping Rules  
The study will be monitored to ensure that the occurrence of a specified set of treatment related serious adverse 
events (TRSAEs) that occur during the treatment period does not substantially exceed an anticipated rate. The 
following specified TRSAEs determined to be probably or definitely related to therapy will be considered for 
early stopping of the study:
1.  Death  
2.  Severe infection requiring vasopressor for >24 hours or intubation 
3.  Any grade 4 toxicity excluding; 

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
Readily reversible metabolic or laboratory abnormalities, and

Hematologic toxicities.
We anticipate the rate of these specified TRSAEs within the first year (completion of primary endpoint) to be 
20% or less. Following Geller et al. (2003, “Design of Early Trials in Stem Cell Transplantation: A Hybrid 
Frequentist-Bayesian Approach”),75 our stopping rule is determined by a Bayesian approach. The stopping 
boundary for an experiment is reached if the Bayesian posterior probability that the true probability of 
developing one or more of the specified TRSAE’s exceeds this benchmark rate of 20% is at least 90%. We take 
our prior distribution to be a beta distribution so that our prior clinical opinion is worth 20% of the weight we 
will place on the new data. This gives prior parameters (α, β) = (1, 4). Hence, when we make decisions about 
stopping the study, the data from the study will dominate over the prior opinion.  We begin monitoring the 
TRSAEs when 3 subjects are evaluable for TRSAEs within 1 year.
Number of  
subjects in the 
experiment
Stop if the number of subjects 
who have developed any of 
the specified TRSAE’s 
reaches:
≤ 5
3
≤ 9
4
≤ 12
5
≤ 16
6
≤ 20
7
≤ 24
8
≤ 25
9
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, we 
generated a study with 25 independent Bernoulli trials, each had a probability p for having TRSAE and q=1-p 
for not having TRSAE and compared the TRSAE outcomes with the above stopping boundary to determine 
whether the study was stopped.  We repeated the simulation 100,000 times and computed the proportion of 
stopped studies (i.e. “number of stopped studies”/100,000) which were stopped using the above stopping rule.  
The following table summarizes the proportions of stopped studies under a number of scenarios for p:
Probability of TRSAE = p
0.1
0.15
0.20
0.25
0.30
0.40
Proportion of Stopped Studies
1.7%
7.9%
18.4%
35.8%
55.4%
86.2%
Average number of subjects
24.7
23.9
22.4
20.1
17.3
11.8
Average number TRSAEs
2.5
3.6
4.5
5.0
5.2
4.7
These results suggest that our stopping rule has a low probability stopping a study when the proportion of 
TRSAE is below the benchmark value of 20%, and the probability of stopping a study is high when the true 
proportion of TRSAE exceeds this benchmark value. Based on these results, we believe that our Bayesian 
stopping rule has satisfactory statistical properties. 
9.6
Stopping rule for Mortality 
In addition, we have a stopping rule for TRM (deaths that are possibly, probably or definitely related to the 
protocol regimen, and are not due to disease progression).  We anticipate the TRM rate within one year to be 

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5% or less. Using the same Bayesian approach, the stopping boundary is reached if the Bayesian posterior 
probability that the true probability of developing TRM’s exceeds 5% is at least 90%.  We take our prior 
distribution to be a beta distribution with parameters (α, β) = (0.25, 4.75). This indicates that the relative weight 
we place on our prior opinion is approximately 20% of the weight we will place on the results of the new study.  
The following table summarizes the threshold numbers for stopping the study based on above Bayesian 
approach.
Number of 
subjects in the 
experiment
Stop if the number of 
subjects who have TRMs 
reaches:
≤ 9
2
≤ 21
3
≤ 25
4
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, we 
generated a study with 30 independent Bernoulli trials, each had a probability p for having TRM and q=1-p for 
not having TRM and compared the TRM outcomes with the above stopping boundary to determine whether the 
study was stopped.  We repeated the simulation 100,000 times and computed the proportion of stopped studies 
(i.e. “number of stopped studies”/100,000) which were stopped using the above stopping rule.  The following 
table summarizes the proportions of stopped studies under a number of scenarios for p:
Probability of TRM = p
0.03
0.05
0.07
0.10
0.15
0.20
Proportion of Stopped Studies
4.2%
12.1%
22.9%
41.4%
68.9%
86.3%
Average number of subjects
24.4
23.3
21.9
19.4
15.2
11.6
Average number TRMs
0.7
1.2
1.5
1.9
2.3
2.3
These results suggest that our stopping rule has a low probability stopping a study when the proportion of 
TRM is below the benchmark value of 5%, and the probability of stopping a study is high when the true 
proportion of TRM exceeds this benchmark value. Based on these results, we believe that our Bayesian 
stopping rule has satisfactory statistical properties. 
9.7
Off Study Criteria (for subject participation)
Patient choice:  Subjects may be removed from the study at their request.  The risks of withdrawing will be 
discussed, as will alternative treatment options. Subjects who opt to withdraw from the protocol will be strongly 
encouraged to continue to have labs monitored for two months after study withdrawal for their safety.  
PI Decision: Patients will be taken off study for:

Initiation of non-protocol treatment.
o
For patients who were newly diagnosed with a second malignancy, the study treatment can be 
temporarily interrupted while the patient undergoes further evaluation and treatment with 
definitive, time-limited systemic therapy. For pembrolizumab, drug interruptions of up to 6 weeks 
are allowed. For ibrutinib, drug interruptions of up to 6 months are allowed during the single-
agent ibrutinib maintenance phase. Longer interruptions in investigational treatment will require 
removal of subjects from the protocol.

Significant progression of disease or a concomitant condition that would make the subject ineligible 

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for further protocol participation 

Pregnancy or begins breast feeding

Subject becomes significantly noncompliant with study drug administration, study procedures, or study 
requirements, which might increase risk or substantially compromise the interpretation of study results.
Completion of the study:  Subjects will be followed indefinitely until an off study criterion is met or the study 
is closed to further follow up care. Once protocol participation is complete, the subject will be referred back to 
his or her referring physician for standard therapy or evaluated for eligibility for another branch protocol, 
depending on what is considered to be in the best interest of the subject.
10.0
DATA AND SAFETY MONITORING
Principal Investigator:  Accrual, efficacy and safety data will be monitored by the principal investigator 
Adrian Wiestner, M.D., Ph.D.
NIH Intramural IRB:  Prior to implementation of this study, the protocol and the proposed patient consent 
and assent forms will be reviewed and approved by the properly constituted Institutional Review Board (IRB) 
operating according to 45 CFR 46. Quality assurance and control monitoring will be consistent with the NHLBI 
Division of Intramural Research Clinical Research Quality Assurance and Quality Control Policy.
NHLBI DSMB:  The NHLBI Data And Safety Monitoring Board (DSMB) will review the protocol, progress 
report, accrual, efficacy and safety data at six- or twelve-month intervals as scheduled.  All AEs and SAEs 
observed during the clinical trial and for which there is a relationship with the use of the ibrutinib, fludarabine 
and pembrolizumab, or the conduct of the study will be reported to the DSMB at the regularly scheduled DSMB 
meeting. The DSMB may recommend early termination of the study for considerations of safety and efficacy. 
Merck: Merck will approve all amendments to the protocol or informed consent prior to submission to the IRB 
and conduct continuing annual review so long as the protocol is open to accrual or sample and/or data analysis 
continues. Accrual and safety data will also be monitored and reviewed annually by the IRB. An annual progress 
report, any amendments to the protocol, and any change in the status of the protocol will be forwarded to Merck 
Global Safety facsimile number: +1-215-993-1220.
Pharmacyclics: Per the IST Agreement, any amendments to the Protocol or Informed Consent Form must be 
sent to Pharmacyclics for review and approval prior to submission to the IRB.
10.1
Assessment of safety
Definitions
Please refer to Policy 801: Reporting Research Events.
10.1.1.   Severity
We will use the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 for 
grading of non-hematologic AEs (http://ctep.cancer.gov/reporting/ctc.html). We will use 2008 International 
Workshop for CLL grading scale for grading of hematologic AEs (Table 11).
Table 11. The grading scale for hematologic AEs in subjects with CLL13

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Grade1
Decrease in platelets2 or Hb3 
(nadir) from pretreatment 
value
Absolute neutrophil count/μL4 
(nadir)
0
No change to 10%
≥ 2000
1
11%-24%
≥ 1500 and < 2000
2
25%-49%
≥ 1000 and < 1500
3
50%-74%
≥ 500 and < 1000
4
≥ 75%
< 500
1.
Grades: 1, mild; 2, moderate; 3, severe; 4, life threatening; 5, fatal.  Death occurring as a result of 
toxicity at any level of decrease from pretreatment will be reported as Grade 5.
2.
Platelet counts must be below normal levels for Grades 1 to 4.  If, at any level of decrease, the platelet 
count is < 20 x 109/L (20,000/μL), this will be considered Grade 4 toxicity, unless a severe or life-
threatening decrease in the initial platelet count (e.g., < 20 x 109/L [20,000/μL]) was present 
pretreatment, in which case the patient is not evaluable for toxicity referable to platelet counts.
2. Hemoglobin (Hb) levels must be below normal levels for Grades 1 to 4. Baseline and subsequent Hb 
determinations must be performed before any given transfusions. The use of erythropoietin is 
irrelevant for the grading of toxicity, but should be documented.
3. If the ANC reaches < 1 x 109/L (1000/μL), it should be judged to be Grade 3 toxicity. Other decreases 
in the white blood cell count, or in circulating neutrophils, are not to be considered because a decrease 
in the white blood cell count is a desired therapeutic endpoint. A gradual decrease in granulocytes is 
not a reliable index in CLL for stepwise grading of toxicity. If the ANC was < 1 x 109/L (1000/μL) 
before therapy, the patient is not evaluable for toxicity referable to the ANC. The use of growth factors 
such as granulocyte colony-stimulating factor (G-CSF) is not relevant to the grading of toxicity, but 
should be documented.
10.1.2 Pregnancy
         
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. However, should 
a pregnancy occur in a female study subject, consent to provide follow-up information regarding the outcome 
of the pregnancy and the health of the infant until 30 days old will be requested.
A female subject must immediately inform the Investigator if she becomes pregnant from the time of consent 
to 90 days after the last dose of study drug. A male subject must immediately inform the Investigator if his 
partner becomes pregnant from the time of consent to 90 days after the last dose of study drug. Any female 
subjects receiving study drug(s) who become pregnant must immediately discontinue study drug. The 
Investigator should counsel the subject, discussing any risks of continuing the pregnancy and any possible 
effects on the fetus. Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent to 90 days 
after the last dose of study drug must be reported. 
Reports to Pharmacyclics
Any occurrence of pregnancy must be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting 
timelines. All pregnancies will be followed for outcome, which is defined as elective termination of the 
pregnancy, miscarriage, or delivery of the fetus. Pregnancies with an outcome of live birth, the newborn infant 
will be followed until 30 days old and this must be reported to Pharmacyclics Drug Safety, or designee, per 

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SAE reporting timelines. Any congenital anomaly/birth defect noted in the infant must be reported as a serious 
adverse event. 
Reports to Merck
The outcome of the pregnancy will be reported to Merck without delay and within 24 hours to the sponsor and 
within 2 working days to Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  Such events must be 
reported to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)
10.1.3 Other malignancies
         
All new malignant tumors including solid tumors, skin malignancies and hematologic malignancies will be 
reported for the duration of study treatment and during any protocol-specified follow-up periods including post-
progression follow-up for overall survival. If observed, enter data in the corresponding eCRF.
10.1.4 Causality assessments
The following general guideline will be followed:
10.2
Adverse Event Documentation 
This study is closed for accrual as of March 9, 2021. The patients remaining on study are continuing 
taking ibrutinib as a single agent, consistent with the standard of care for CLL. 
The protocol will no longer capture new AEs. 
The protocol will continue to collect following events on study:
- SAEs and UPs defined by Policy 801
- Events of special interest (as defined in Section 10.8)
If an SAE is present at the safety follow-up visit or within 30 days of the last dose of study drug (whichever is 
later), it should be followed to resolution or until the Investigator assesses the subject as stable, a new anticancer 
Unrelated
Another cause of the AE is more plausible; a temporal sequence cannot be established 
with the onset of the AE and administration of the investigational product; or, a causal 
relationship is considered biologically implausible.
Unlikely to be 
Related:
A temporal sequence with the onset of the adverse event and administration of the 
investigational product is improbable, but not impossible. Concurrent or underlying 
disease, or the use of other drugs or procedures provide plausible explanations for the 
adverse event.
Possibly Related
There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the adverse event could also be 
attributed to concurrent or underlying disease, or the use of other drugs or procedures. 
Possibly related should be used when the investigational product is one of several 
biologically plausible adverse event causes.
Probably Related:
There is a clinically plausible time sequence between onset of the adverse event and 
administration of the investigational product, and the adverse event is unlikely to be 
attributed to concurrent or underlying disease, or the use of other drugs or procedures. 
Clinical response to withdrawal of the investigational product may indicate the adverse 
event is probably related. Rechallenge with the investigational drug is not required.
Definitely Related
The AE is clearly related to use of the investigational product.

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therapy is initiated, or the subject is lost to follow-up or withdraws consent. Resolution/stable means the subject 
has returned to baseline state of health or the Investigator does not expect any further improvement or worsening 
of the event.
10.3
NIH Intramural IRB and CD reporting
Expedited Reporting
Events requiring expedited reporting will be submitted to the IRB per Policy 801.
Reports to the IRB at the time of Continuing Review
The PI or designee will refer to Policy 801.
Reports to the CD
The PI or designee will refer to NHLBI DIR Policy to determine CD reporting requirements and timelines.
10.4
Reports to Merck
An SAE is any AE occurring at any dose or during any use of Merck’s product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is a new cancer (that is not a condition of the study);

Is associated with an overdose;

Is another important medical event.
 
Any SAE, or follow up to a SAE, including death due to any cause other than progression of the cancer under 
study that occurs to any subject from the time the consent is signed through 90 days following cessation of 
treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck 
product, must be reported within 24 hours to the sponsor and within 2 working days to Merck Global Safety. 
Additionally, any SAE, considered by an investigator who is a qualified physician to be related to Merck 
product that is brought to the attention of the investigator at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor and to Merck.
SAE reports and any other relevant safety information are to be forwarded to the Merck Global Safety 
facsimile number:  +1-215-993-1220
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European Union 
(EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. Investigators will 
cross-reference this submission according to local regulations to the Merck Investigational Compound 
Number (IND, CSA, etc.) at the time of submission.  Additionally, investigators will submit a copy of these 
reports to Merck at the time of submission to FDA.
All adverse events will be recorded from the time the consent form is signed through 30 days following 
cessation of treatment and at each examination on the adverse event case report forms/worksheets. 

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10.5
Reports to Pharmacyclics LLC, an AbbVie Company
Special reporting situation on a Sponsor study may require expedited reporting and/or safety evaluation include, 
but are not limited to:

Overdose of any study drug

Suspected abuse/misuse of a study drug

Inadvertent or accidental exposure to a study drug

Medication error involving a product (with or without subject exposure to the study drug, eg, name 
confusion)
All serious adverse events and adverse events of special interest (initial and follow-up information) will be 
reported on FDA Medwatch (Form 3500A) or Suspect Adverse Event Report (CIOMS Form 1) IRB Reporting 
Form and sent via email (AEintakeCT@pcyc.com) or fax (+1-408-215-3500) to Pharmacyclics Drug 
Safety, or designee, within 15 days of the event. Pharmacyclics may request follow-up and other additional 
information from the Sponsor Investigator.
Pharmacyclics LLC, an AbbVie Company, will be notified for Drug Safety, or designee of any serious, 
unexpected, fatal or life-threatening adverse event or adverse drug reaction as soon as possible, but no later 
than 7 calendar days in the case of death or life-threatening serious adverse events after the Sponsor’s receipt 
of the information or becoming aware of the occurrence. All other SAEs will be reported no later than 15 days 
after the Sponsor’s receipt of the information or becoming aware of the occurrence. Pharmacyclics LLC  may 
request follow-up and other additional relevant clinical records or information from the investigator.  The 
Sponsor will submit each IND safety report in a format that complies with the FDA reporting requirements. A 
copy of this IND safety report must also be faxed concurrently to Pharmacyclics Drug Safety.
10.6
Reporting Period for AEs
The AE reporting period for this study begins when the patient takes the first dose of study drug and ends with 
the safety follow-up visit. If an SAE is present at the safety follow-up visit or within 30 days of the last dose of 
study drug (whichever is later), it should be followed to resolution or until the Investigator assesses the subject 
as stable, a new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws consent. 
Resolution/stable means the subject has returned to baseline state of health or the Investigator does not expect 
any further improvement or worsening of the event.
10.7
Reporting for other malignancies
All new malignant tumors including solid tumors, skin malignancies and hematologic malignancies had been 
reported as SAEs until January 2019. This was based on the assumption that malignancies are medically 
significant events that impact patient survival. However, non-melanoma skin cancer, such as squamous cell or 
basal cell carcinoma of skin, is most often managed with local resection only and has minimal impact on long-
term survival. As of February 2019, this protocol no longer considers non-melanoma skin cancer as a SAE. 
Other malignancies, including malignant melanoma and other solid tumors, will be continued to be reported as 
SAEs.
10.8 
Events of clinical interest
Merck

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Selected non-serious and serious AEs are also known as Events of Clinical Interest (ECI) and must be recorded 
as such on the AE case report forms/worksheets and reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220). Events of clinical 
interest for this trial include:
Overdose: An overdose of pembrolizumab is defined a as any dose of 1,000 mg or greater ( ≥5 times the 
indicated dose). No specific information is available on the treatment of overdose of pembrolizumab. 
Appropriate supportive treatment should be provided if clinically indicated. In the event of overdose, the subject 
should be observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. If an AE is associated with the overdose of pembrolizumab, the AE is reported as a serious 
adverse event, even if no other seriousness criteria are met. If a dose pembrolizumab meeting the protocol 
definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the 
overdose is reported as a non-serious ECI, using the terminology “accidental or intentional overdose without 
adverse effect.” All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 993-1220)
Elevation of AST, ALT, bilirubin, alkaline phosphatase: An elevated AST or ALT lab value that is greater than 
or equal to 3X the upper limit of normal (ULN) and an elevated total bilirubin lab value that is greater than or 
equal to 2X the ULN and, at the same time, an alkaline phosphatase lab value that is less than 2X the ULN, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of the criteria is 
to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying 
etiology.  The trial site guidance for assessment and follow up of these criteria can be found in the Investigator 
Trial File Binder (or equivalent).
Pharmacyclics
Adverse Events of Special Interest (AESI)
Specific adverse events, or groups of adverse events, will be followed as part of standard safety monitoring 
activities by the Sponsor. These events (regardless of seriousness) will be reported to Pharmacyclics Drug 
Safety, or designee within 15 days of awareness.  
Major Hemorrhage
Major hemorrhage is defined as any of the following:

Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher. All hemorrhagic events 
requiring transfusion of red blood cells should be reported as grade 3 or higher AE per CTCAE v4.03 

Any treatment-emergent serious adverse events of bleeding of any grade

Any treatment-emergent central nervous system hemorrhage/hematoma of any grade
Events meeting the definition of major hemorrhage will be captured as an event of special interest according to 
above.
10.9
Data management 
The principal investigator will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal investigator, associate 

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investigators/research nurses and/or a contracted data manager will assist with the data management efforts to 
ensure that data is verifiable and evaluable. Data will be abstracted from Clinical Center progress notes as well 
as from progress notes forwarded from the subjects’ home physician. Laboratory data from NIH will be 
imported electronically from CRIS into an in-house clinical trial database. Laboratory values from referring 
home physicians will be entered into the system. 
We will maintain the confidentiality of identifiable private information collected in this Clinical Trial and 
protect the privacy of the individual human subjects. Primary data containing individually identifiable 
information obtained during the conduct of the protocol will be kept in secure network drives or in approved 
alternative sites that comply with NIH information security standards. Neither individual personal identifiers 
nor the key linking coded data to individuals will be released to Merck without prior IRB approval and an 
executed CDA or MTA. Identifiable data will not be sent outside NIH without prior IRB approval or appropriate 
conditions for disclosure outlined in the executed CDA or MTA.
End of study procedures:  Data will be stored in locked cabinets and in a password protected database until it 
is no longer of scientific value. Upon completion of the data analysis, the investigator will send to Merck a copy 
of the de-identified data set and final Clinical Study Report as requested. 
Loss or destruction of data:  Should we become aware that a major breech in our plan to protect patient 
confidentiality and trial data has occurred, the IRB will be notified.
10.10        Protocol Amendments
Per the IST Agreement, any amendments to the protocol or informed consent form must be sent to Merck and 
Pharmacyclics for review and approval prior to submission to the IRB.  Written verification of IRB approval 
will be obtained before any amendment is implemented.
Publication Policy: Given the research mandate of the NIH, patient data including the results of testing and 
responses to treatment will be entered into an NIH-authorized and controlled research database. Any future 
research use will occur only after appropriate human subject protection institutional approval such as 
prospective NIH IRB review and approval or an exemption from the NIH Office of Human Subjects Research 
Protections (OHSRP).
Per the IST Agreement, the Investigator is required to submit to Merck and Pharmacyclics a copy of a planned 
publication (abstract, poster, oral presentation or manuscript) prior to the submission thereof for publication or 
disclosure.  Merck and Pharmacyclics may provide scientific comments and suggestions understanding that the 
Investigator has sole editorial responsibility, and retains the authority to make the final determination on 
whether or not to incorporate Merck and Pharmacyclics comments or requests for additional information.
10.11 
Protocol Monitoring 
As per ICH-GCP 5.18 and FDA 21 CFR 312.5, clinical protocols are required to be adequately monitored by 
the study sponsor. The monitoring of this study will be conducted by Clinical Research Associates 
(CRAs)/Monitors working under an agreement with NHLBI to monitor aspects of the study in accordance with 
the appropriate regulations and the approved protocol. The objectives of a monitoring visit will be: 1) to verify 
the existence of signed informed consent form (ICF) and documentation of the ICF process for each monitored 
subject; 2) to verify the prompt and accurate recording of all monitored data points, and prompt reporting of all 
SAEs; 3) to compare abstracted information with individual subjects’ records and source documents (subject’s 

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charts, laboratory analyses and test results, physicians’ progress notes, nurses’ notes, and any other relevant 
original subject information); and 4) to help ensure investigators are in compliance with the protocol. The 
monitors also will inspect the clinical site regulatory files to ensure that regulatory requirements (Office for 
Human Research Protections-OHRP), FDA and applicable guidelines (ICH-GCP) are being followed. During 
the monitoring visits, the investigator (and/or designee) and other study personnel will be available to discuss 
the study progress and monitoring visit.
The investigator (and/or designee) will make study documents (e.g., consent forms and pertinent hospital or 
clinical records readily available for inspection by the local IRB, the FDA, the site monitors, and the NHLBI 
staff for confirmation of the study data.
11.0
HUMAN SUBJECT PROTECTION 
The investigator(s) accept their responsibilities for protecting the rights and welfare of human research subjects 
and will permit, with reasonable advance notice and at reasonable times, the designated research monitors to 
monitor the conduct of the research, as well as to audit source documents to the extent necessary to verify 
compliance with FDA Good Clinical Practice and the approved protocol.
11.1
Rationale for subject selection
11.1.1 Predicted distribution by gender, age and race
CLL is a rare neoplasm that comprises a substantial proportion of all leukemia in middle-aged persons and is 
the most common type among elderly persons in western populations.  Epidemiologic studies suggest that 
distribution by gender will be 66% males and 33% females.13 CLL is more common in Caucasian and African-
American but rare in Hispanics and very rare in the Asian population. This study will be open to all patients 
who fit the inclusion criteria and provide informed consent to protocol participation. We would predict that 
distribution should be comparable to that seen on the NHLBI Hematology Branch screening protocol as follows: 

by gender: 33% females; 66% males

by age: ages 23-79, median 60  

by race: 2% Asian, 11% Black, 8% Hispanic, 79% White
11.1.2 Special Populations 
Justification for inclusion of high-risk and/or relapsed/refractory CLL: Ibrutinib is FDA-approved for the 
treatment of high-risk CLL with deletion 17p regardless of treatment status and for relapsed/refractory CLL. 
However, treatment with a single-agent ibrutinib lacks the depth of response, and resistant mutations can occur. 
By combining ibrutinib with short-course fludarabine and pembrolizumab, this study aims to augment the 
quality of response and prevent drug resistance in patients with high-risk cytogenetic mutations or who have 
relapsed/refractory CLL. 
Justification for exclusion of children: CLL is uncommon in patients less than 45 years of age and is virtually 
unknown in patients less than 20 years of age. At the time of diagnosis, more than 95% of patients are 45 years 
old and above.11 CLL may also be, biologically, a different disease in children.  Ibrutinib has not been studied 
in human subjects under 18 years of age. For these reasons, individuals < 18 years old have been excluded from 
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Justification for exclusion of pregnant women: There are no clinical studies that were done on pregnant 
women, and it is unknown whether ibrutinib, pembrolizumab or their metabolites are excreted in human milk. 
In addition, it is highly unlikely that a woman of pre-menopausal age will present with CLL or SLL at the 
Clinical Center. CLL/SLL is a malignancy of B cells that predominantly affects the elderly population. 
Diagnosis is typically made in adults over the age of 50 and more than half of the people with CLL/SLL are 
over the age of 70. 
Justification for exclusion of patients with impaired hepatic or renal function: No specific clinical studies 
have been conducted to date in patients with impaired hepatic or renal function. To minimize risks, patients 
enrolled must have adequate hepatic and renal function as defined in eligibility and exclusion criteria.
Adults with decisional impairment: Adults unable to give consent are excluded from enrolling in the protocol. 
However, reconsent may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. Because there is a prospect of direct benefit from research participation those subjects 
will be allowed to continue study participation. For this reason all subjects ≥ age 18 will be offered the 
opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another person can make 
decisions about their medical care in the event that they become incapacitated or cognitively impaired during 
the course of the study. Note: The PI or AI will follow Policy 403 and contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify an LAR as 
needed. 
Please note that if a subject loses the ability to consent due to an adverse event/serious adverse event, the subject 
will remain on study until that event resolves and will be allowed to continue to participate in this trial.  
Recruitment: A Strategic Recruitment Plan (SRP) has been developed in conjunction with the NHLBI Patient 
Recruitment Office. Recruitment strategies that will be ongoing throughout recruitment period of trial may 
include 1) distribution of a recruitment flyer in the NIH campus, patient advocacy organizations and the 
community; 2) updating study information on clinicaltrials.gov, NIH Search the Studies, and a dedicated 
recruitment page on the Clinical Center Office of Patient Recruitment website; 3) the use of ResearchMatch for 
identification of study candidates; 4) promoting the study on the official NIH social media account with IRB 
approved language and images; 5) distribution of a recruitment information on NIH listservs; and 7) distribution 
of a physician-to-physician letter to local hematologists/oncologists.
     
Payment for participation:  $0 – Subjects will not be compensated for their participation in this study. There is 
no payment for the blood samples obtained for research.
Reimbursement for protocol participation travel, food, and lodging will be consistent with NIH guidelines.  
For travel from home:  Travel from home for the first NIH visit will not be reimbursable. If the patient 
consents to protocol participation travel home following the first visit will be reimbursable. Subjects will be 
reimbursed 100% of government rate for travel once the subject has been determined eligible to participate and 
signs consent.
Local travel (car/taxi/shuttle/train/bus):  Subjects will be reimbursed for local train/bus and/or shuttle costs 
consistent with NIH guidelines.  Car mileage will be reimbursed $0.41/mile when the distance from home is 

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greater than 50 miles. Reimbursement for mileage less than 50 miles from home is not provided. Subjects will 
not be reimbursed for rental car cost beyond the car mileage rate. Taxi will be paid only when medically 
necessary and authorized by the PI.
Meals: Subjects will not be reimbursed for meals.
Lodging:  Will be consistent with NIH guidelines.  
Competition with other Branch protocols: There is no active treatment protocol specifically designed for 
treatment-naïve CLL/SLL patients with high-risk genetic markers. Approximately 10% of treatment-naïve 
CLL patients will be eligible for the current protocol. 
11.2
Risks and discomforts related to research 
11.2.1 Risks related to ibrutinib
Bleeding-related events
There have been reports of bleeding events in subjects treated with ibrutinib both with and without 
thrombocytopenia.  These include primarily minor bleeding events such as contusion, epistaxis, eye 
hemorrhage, and petechiae; and major bleeding events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage and hematuria. In an in vitro platelet function study, inhibitory effects of ibrutinib on 
collagen-induced platelet aggregation were observed. Use of  either anticoagulant or antiplatelet agents 
concomitantly with ibrutinib increases the risk of major bleeding. A higher risk for major bleeding was observed 
with anticoagulant than with antiplatelet agents. Consider the risks and benefits of anticoagulant or antiplatelet 
therapy when co-administered with ibrutinib. Monitor for signs and symptoms of bleeding. Supplements such 
as fish oil and vitamin E preparations should be avoided.
Subjects with congenital bleeding diathesis have not been studied. See Section 5.6.3  for guidance on 
concomitant use of anticoagulants, antiplatelet therapy and/or supplements. Ibrutinib should be held at least 3 
to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding. See Section 5.4.1 
for guidance on ibrutinib management with surgeries or procedures.
Cardiac arrhythmias 
Fatal and serious cardiac arrhythmias or cardiac failure have occurred in patients treated with ibrutinib. Patients 
with significant cardiac comorbidities may be at greater risk of events, including sudden fatal cardiac events. 
Atrial fibrillation, atrial flutter, ventricular tachyarrhythmia and cardiac failure,  have been reported, particularly 
in subjects with acute infections, or cardiac risk factors, including hypertension, diabetes mellitus, and a 
previous history of cardiac arrhythmia.. Appropriate clinical evaluation of cardiac history and function should 
be performed prior to initiating ibrutinib. Patients should be carefully monitored during treatment for signs of 
clinical deterioration of cardiac function and clinically managed. Consider further evaluation (e.g., ECG, 
echocardiogram), as indicated for patients in whom there are cardiovascular concerns. For signs and symptoms 
that persist, consider the risks and benefits of ibrutinib treatment and follow the protocol dose modification 
guideline (see Section 5.4.2).
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Although causality has not been established, cases of cerebrovascular accident, transient ischemic attack, and 
ischemic stroke including fatalities have been reported with the use of ibrutinib in the post-marketing setting, 
with and without concomitant atrial fibrillation and/or hypertension. Regular monitoring and appropriate 
treatment of conditions that can contribute to the occurrence of these events is recommended.
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were reported in 
subjects treated with ibrutinib. 
Gastrointestinal disorders
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and combination 
therapy. Other frequently reported gastrointestinal events include nausea, vomiting, dyspepsia, and 
constipation. These events are rarely severe and are generally managed with supportive therapies including 
antidiarrheals and antiemetics. Subjects should be monitored carefully for gastrointestinal AEs and cautioned 
to maintain fluid intake to avoid dehydration. Medical evaluation may include tests to rule out other etiologies 
such as Clostridium difficile or other infectious agents. Should symptoms be severe or prolonged follow the 
protocol dose modification guidelines (see Section 5.4).
Hypertension
Hypertension has occurred in subjects treated with ibrutinib. Regularly monitor blood pressure in subjects 
treated with ibrutinib and initiate or adjust antihypertensive medication throughout as appropriate.
Infections
Infections (including sepsis, bacterial, viral, or fungal infections such as Pneumocystis pneumonia and 
aspergillosis) were observed in subjects treated with ibrutinib therapy. Some of these reported infections have 
been associated with hospitalization and death. Consider prophylaxis according to standard of care in subjects 
who are at increased risk for opportunistic infections. Although causality has not been established, cases of 
progressive multifocal leukoencephalopathy (PML) and hepatitis B reactivation and pneumocystis pneumonia 
have occurred in patients treated with ibrutinib. Cases of hepatitis E, which may be chronic, have occurred in 
patients treated with ibrutinib. Subjects should be monitored for signs and symptoms (such as fever, chills, 
weakness, confusion, vomiting, jaundice, and abnormal liver function tests) and appropriate therapy should be 
instituted as indicated
Tumor lysis syndrome (TLS)
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single-agent ibrutinib 
or in combination with chemotherapy. Subjects at risk of TLS are those with high tumor burden prior to 
treatment.
Non-melanoma skin cancer
Non-melanoma skin cancers have occurred in patients treated with ibrutinib. Monitor patients for the 
appearance of non-melanoma skin cancer.
Rash
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in combination with 
chemotherapy. Most rashes were mild to moderate in severity. Isolated cases of severe cutaneous adverse 
reactions (SCARs) including Stevens-Johnson syndrome (SJS) have been reported in subjects treated with 

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ibrutinib. Neutrophilic dermatosis has been reported in postmarketing surveillance. Subjects should be closely 
monitored for signs and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected agent as 
appropriate. In addition, hypersensitivity-related events including erythema, urticaria, and angioedema have 
been reported.
Interstitial lung disease
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. Subjects should be 
monitored and evaluated for symptoms indicative of ILD (eg, dyspnea, cough or pyrexia). If symptoms develop, 
interrupt ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines.
Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high number of circulating 
lymphocytes (>400,000/µL) may confer increased risk of leukostasis. Consider temporarily withholding 
ibrutinib. Subjects should be closely monitored. Administer supportive care such as hydration and/or 
leukapheresis as indicated. 
Lymphocytosis
Upon initiation of single-agent treatment with ibrutinib, a reversible increase in lymphocyte counts (i.e., ≥50% 
increase from baseline and an absolute count >5000/µL), often associated with reduction of lymphadenopathy, 
has been observed in most subjects (66%) with CLL/SLL. This effect has also been observed in some subjects 
(33%) with mantle cell lymphoma (MCL) treated with ibrutinib. This observed lymphocytosis is a 
pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical 
findings. In both disease types, lymphocytosis typically occurs during the first month of ibrutinib therapy and 
typically resolves within a median of 8 weeks in subjects with MCL and 14 weeks in subjects with CLL/SLL 
(range, 0.1 to 104 weeks). 
When ibrutinib was administered in combination with BR or with obinutuzumab in subjects with CLL/SLL, 
lymphocytosis was infrequent (7% with ibrutinib + BR versus 6% with placebo + BR and 7% with ibrutinib + 
obinutuzumab versus 1% with chlorambucil + obinutuzumab). Lymphocytosis was not commonly observed in 
subjects with Waldenström’s macroglobulinemia treated with ibrutinib.
Long-term safety
The long-term safety data over 5 years from 1,284 subjects (treatment-naïve CLL/SLL n = 162, 
relapsed/refractory CLL/SLL n=646, relapsed/refractory MCL n = 370, and WM n=106) treated with ibrutinib 
were analyzed. The median duration of treatment for CLL/SLL was 51 months (range, 0.2 to 98 months) with 
70% and 52% of subjects receiving treatment for more than 2 years and 4 years, respectively. The median 
duration of treatment for MCL was 11 months (range, 0 to 87 months) with 31% and 17% of subjects receiving 
treatment for more than 2 years and 4 years, respectively. The median duration of treatment for WM was 47 
months (range, 0.3 to 61 months) with 78% and 46% of subjects receiving treatment for more than 2 years and 
4 years, respectively. The overall known safety profile of ibrutinib-exposed subjects remained consistent, other 
than an increasing prevalence of hypertension, with no new safety concerns identified. The prevalence for Grade 
3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2-3), 9% (year 3-4), and 9% (year 4-5). 
The overall incidence for the 5-year period was 11%.

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Potential for drug-drug interactions 
Ibrutinib is primarily metabolized by CYP3A4.. Of the 3,838 subjects with hematologic malignancies in the 
RSI pool, 51.9% took at least one CYP3A inhibitor at any time during a study; 9.2% used a strong CYP3A 
inhibitor, 28.5% used a moderate CYP3A inhibitor, and 32.6% used a weak CYP3A inhibitor (Appendix H of 
the IB v.15). The strong CYP3A inhibitors used were clarithromycin (5.0%), voriconazole (3.2%), 
posaconazole (0.7%), itraconazole (0.5%), and ketoconazole (0.1%). The most commonly used moderate 
CYP3A inhibitors (≥1% of subjects) were fluconazole (5.2%), ciprofloxacin (15.4%), diltiazem (2.4%), and 
aprepitant (1.6%). The most commonly used weak CYP3A inhibitors (≥2% of subjects) were amlodipine 
(8.2%), atorvastatin (6.5%), ranitidine (6.1%), alprazolam (4.6%), amiodarone (3.0%), ranitidine hydrochloride 
(2.7%), amlodipine besilate (2.2%), atorvastatin calcium (2.0%).
Of the 214 subjects with cGVHD in the RSI pool, 98.6 % took at least 1 CYP3A inhibitor; 60.3% used a strong 
CYP3A inhibitor, 46.7% used a moderate CYP3A inhibitor, and 90.7% used a weak CYP3A inhibitor. The 
strong CYP3A inhibitors used were posaconazole (33.2%), voriconazole (29.0%), clarithromycin (3.7%), and 
itraconazole (3.7%). The most commonly used moderate CYP3A inhibitors (≥1% of subjects) were fluconazole 
(30.4%), ciprofloxacin (9.8%), imatinib (8.4%),  isavuconazonium (2.3%), and erythromycin (1.9%). The most 
commonly used weak CYP3A inhibitors (≥2% of subjects) were tacrolimus (52.8%), ciclosporin (39.7%), 
amlodipine (21.0%), ranitidine (6.5%), atorvastatin (5.6%), alprazolam (3.3%), amiodarone (3.3%), and 
tacrolimus monohydrate (3.3%). 
Agents that may increase ibrutinib plasma concentrations (CYP3A inhibitors):
Concomitant use of ibrutinib and drugs that strongly or moderately inhibit CYP3A can increase ibrutinib 
exposure and strong CYP3A inhibitors should be avoided. 
Strong CYP3A inhibitors
Co-administration of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects, increased exposure 
(Cmax and AUC0-last) of ibrutinib by 29- and 24-fold, respectively. In a dedicated drug-drug interaction study 
in subjects with B-cell malignancies, co-administration of voriconazole increased ibrutinib Cmax and AUC by 
6.7-fold and 5.7-fold, respectively. In clinical studies, the maximal observed ibrutinib exposure (AUC) was ≤ 
2-fold in 37 subjects treated with mild and/or moderate CYP3A inhibitors when compared with the ibrutinib 
exposure in 76 subjects not treated concomitantly with CYP3A inhibitors. Clinical safety data in 66 patients 
treated with moderate (n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful increases in 
toxicities. Voriconazole and posaconazole can be used concomitantly with ibrutinib as per the dosing guidance 
described in the specific clinical study protocol. All other strong inhibitors of CYP3A (eg, ketoconazole, 
indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone and 
cobicistat) should be avoided, and an alternative with less CYP3A inhibitory potential should be considered. If 
the benefit outweighs the risk and a strong CYP3A inhibitor must be used, see the recommended dose 
modifications described in the specific clinical study protocol.
Moderate and mild CYP3A inhibitors
In subjects with B-cell malignancies, co-administration of the CYP3A inhibitor erythromycin increased Cmax 
and AUC by 3.4-fold and 3.0-fold, respectively. Follow dose modifications described in the ibrutinib USPI. 
No dose adjustment is required in combination with mild inhibitors. Monitor subjects closely for toxicity and 
follow dose modification guidance as needed. Avoid grapefruit and Seville oranges during ibrutinib treatment 
as these contain moderate inhibitors of CYP3A.

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Agents that may decrease ibrutinib plasma concentrations (CYP3A inducers) 
Administration of ibrutinib with strong inducers of CYP3A decreases ibrutinib plasma concentrations by up to 
90%. Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin and St. John’s 
Wort). Consider alternative agents with less CYP3A induction.
Drugs that may have their plasma concentrations altered by ibrutinib
In vitro studies indicated that ibrutinib is a weak reversible inhibitor of CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A4/5 and does not display time--dependent CYP450 inhibition. The 
dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, and CYP2D6. 
Both ibrutinib and the dihydrodiol metabolite are at most weak inducers of CYP450 isoenzymes in vitro. 
However, in a drug interaction study in patients with B cell malignancies, a single 560 mg dose of ibrutinib did 
not have a clinically meaningful effect on the exposure of the CYP3A4 substrate midazolam. In the same study, 
2 weeks of treatment with ibrutinib at 560 mg daily had no clinically relevant effect on the pharmacokinetics 
of oral contraceptives (ethinyl estradiol and levonorgestrel), the CYP3A4 substrate midazolam, nor the 
CYP2B6 substrate bupropion.
In vitro studies indicated that ibrutinib is not a substrate of P-gp, nor other major transporters, except OCT2. 
The dihydrodiol metabolite and other metabolites are P-gp substrates. Ibrutinib is a mild inhibitor of P-gp and 
breast cancer resistance protein (BCRP). Ibrutinib is not expected to have systemic drug-drug interactions with 
P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp and BCRP after a 
therapeutic dose. There are no clinical data available. To minimize the potential for an interaction in the GI 
tract, narrow therapeutic range P-gp or BCRP substrates such as digoxin or methotrexate should be taken at 
least 6 hours before or after ibrutinib. Ibrutinib may also inhibit BCRP systemically and increase the exposure 
of drugs that undergo BCRP -mediated hepatic efflux, such as rosuvastatin.
Based on preliminary data from the combination studies of ibrutinib and venetoclax, venetoclax exposure 
(AUC0-24) at 400 mg daily was approximately 1.8-fold higher with 420 mg ibrutinib in one study (Study 1142, 
CLL, N=131) and approximately 3-fold higher with 560 mg ibrutinib in another study (Study 1143, MCL, 
N=18) compared to available venetoclax single agent 400 mg daily exposure data. In the ibrutinib and 
venetoclax combination study CLL3011, venetoclax trough concentrations were higher in combination with 
ibrutinib (1,765 ng/mL) compared with monotherapy based on historical data (mean range of 630 to 810 ng/mL) 
(NDA/BLA Multi-disciplinary Review and Evaluation Supplemental 2016). It must be noted that the variability 
in pharmacokinetic parameters observed in Study 1142 (%CV of 66%), Study CLL3011 (%CV of 89%) and 
reported in Roberts et al (%CV of 57% and 66% in 2 different 400 mg cohorts) was high. No apparent effect 
on ibrutinib exposure has been noted in Study 1142, while in Study 1143 a higher mean ibrutinib exposure has 
been observed; however, the exposure was within the exposure range of 560 mg ibrutinib observed with 
monotherapy. To date, no new safety signals have been identified in these ongoing combination therapy studies. 
Subjects should be closely monitored for signs of toxicity.
Contraindications
Ibrutinib is contraindicated in subjects with clinically significant hypersensitivity to any of the compound’s 
structural components. Ibrutinib has not been used in subjects with biliary obstruction, acute hepatitis, severe 
liver failure, or severely impaired renal function; hence, avoid use of ibrutinib in patients with these conditions.
Registration and marketing experience

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The company reviewed safety data from clinical trials and postmarketing reports as part of routine surveillance. 
Eye hemorrhage and dyspepsia were recently identified as new adverse reactions in the postmarketing setting 
since the last version of the IB. 
11.2.2 Risks related to fludarabine
Safety data for fludarabine is generated from treatment trials using fludarabine for up to 6 cycles in CLL. In the 
current study, fludarabine is given as a short-course over two cycles only. Nevertheless, all of the known adverse 
events related to fludarabine are listed based on available data. Details of the adverse events can be found in 
the FDA-approved label for fludarabine.
Common side effects: The most common side effects, reported in 1 out of every 3-4 patients, are anorexia, 
nausea, vomiting, muscle pain, tiredness, weakness, and general body discomfort.
Serious side effects:  Most of the side effects seen in patients taking fludarabine are mild to moderate in 
severity. However, severe side effects have occurred, and some had been severe enough to stop fludarabine, 
modify the dose of fludarabine, or led to hospitalization, disability, or death. The following rare but serious side 
effects have been reported in less than 1 in 100 patients; severe allergic reactions (rash; hives; itching; difficulty 
breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; black, tarry, 
or bloody stools; blood in the urine; changes in strength or walk; chest pain; confusion; coughing or vomiting 
blood; difficult or painful urination; fainting; hearing loss; irregular heartbeat; lower back or side pain; mental 
or mood changes (i.e. agitation, confusion); numbness or tingling in the hands or feet; red, swollen, blistered, 
or peeling skin; seizures; severe or persistent tiredness or weakness; signs of infection (i.e. fever, chills, cough, 
or sore throat); shortness of breath; skin changes; sores on the mouth or lips; swelling of the fingers, hands, or 
feet; unusual bruising or bleeding; vision changes or blindness; yellowing of the eyes or skin. Patients will be 
advised to contact the research team immediately in the event of a severe side effect.
11.2.3 Risks related to pembrolizumab
Immune-mediated pneumonitis
Pneumonitis occurred in 139 (3.6%) patients, including Grade 2, 3, 4 or 5 cases in 56 (1.5%), 38 (1.0%), 9 
(0.2%) and 5 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis 
was 3.7 months (range 2 days to 21.3 months). The median duration was 2.1 months (range 1 day to 17.2+ 
months). Pneumonitis led to discontinuation of pembrolizumab in 60 (1.6%) patients. Pneumonitis resolved in 
81 patients, 1 with sequelae.
Immune-mediated colitis
Colitis occurred in 71 (1.9%) patients, including Grade 2, 3 or 4 cases in 15 (0.4%), 44 (1.1%) and 3 (<0.1%) 
patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 3.6 months (range 7 
days to 16.2 months). The median duration was 1.3 months (range 1 day to 8.7+ months). Colitis led to 
discontinuation of pembrolizumab in 18 (0.5%) patients. Colitis resolved in 61 patients. . 
Immune-mediated hepatitis
Hepatitis occurred in 23 (0.6%) patients, including Grade 2, 3 or 4 cases in 4 (0.1%), 16 (0.4%) and 2 (<0.1%) 
patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 1.3 months (range 
8 days to 21.4 months). The median duration was 1.5 months (range 8 days to 20.9+ months). Hepatitis led to 
discontinuation of pembrolizumab in 7 (0.2%) patients. Hepatitis resolved in 19 patients.

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Immune-mediated nephritis
Nephritis occurred in 15 (0.4%) patients, including Grade 2, 3 or 4 cases in 3 (0.1%), 10 (0.3%) and 1 (<0.1%) 
patients, respectively, receiving pembrolizumab. The median time to onset of nephritis was 4.9 months (range 12 
days to 12.8 months). The median duration was 1.8 months (range 10 days to 10.5+ months). Nephritis led to 
discontinuation of pembrolizumab in 7 (0.2%) patients. Nephritis resolved in 9 patients.
Immune-mediated endocrinopathies 
Hypophysitis occurred in 21 (0.5%) patients, including Grade 2, 3 or 4 cases in 6 (0.2%), 12 (0.3%) and 1 
(<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypophysitis was 3.7 
months (range 1 day to 17.7 months). The median duration was 3.3 months (range 4 days to 12.7+ months). 
Hypophysitis led to discontinuation of pembrolizumab in 6 (0.2%) patients. Hypophysitis resolved in 10 
patients, 2 with sequelae.
Hyperthyroidism occurred in 135 (3.5%) patients, including Grade 2 or 3 cases in 32 (0.8%) and 4 (0.1%) 
patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months 
(range 1 day to 21.9 months). The median duration was 2.1 months (range 10 days to 15.5+ months). 
Hyperthyroidism led to discontinuation of pembrolizumab in (0.1%) patients. Hyperthyroidism resolved in 104 
(77%) patients, 1 with sequelae.
Hypothyroidism occurred in 345 (9.0%) patients, including Grade 2 or 3 cases in 251 (6.6%) and 4 (0.1%) 
patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.5 months 
(range 1 day to 18.9 months). The median duration was not reached  (range 2 days to 29.9+ months). One 
patient (< 0.1%) discontinued pembrolizumab due to hypothyroidism. Hypothyroidism resolved in 81 (23%) 
patients, 6 with sequelae. In patients with cHL (n=241) the incidence of hypothyroidism was 14.1% (all Grades) 
with 0.4% Grade 3.
Out of a total of 1562 subjects, adrenal insufficiency was reported for 2 subjects (0.1%). Both events were 
identified as Grade 3 acute event and were considered by the Investigators to be serious and not drug related. 
Severe skin reactions
Immune-related severe skin reactions occurred in 63 (1.6%) patients, including Grade 2 or 3 cases in 4 (0.1%) 
and 52 (1.4%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin 
reactions was 2.5 months (range 4 days to 21.5 months). The median duration was 2.0 months (range 3 days to 
17.8+ months). Severe skin reactions led to discontinuation of pembrolizumab in 6 (0.2%) patients. Severe skin 
reactions resolved in 41 patients. Rare cases of SJS and TEN, some of them with fatal outcome, have been 
observed.  
Complications of allogeneic HSCT in classical Hodgkin lymphoma
Of 23 patients with classic Hodgkin lymphoma who proceeded to allogeneic HSCT after treatment with 
pembrolizumab, 6 patients (26%) developed GVHD, one of which was fatal, and 2 patients (9%) developed 
severe hepatic VOD after reduced-intensity conditioning, one of which was fatal. The 23 patients had a median 
follow-up from subsequent allogeneic HSCT of 5.1 months (range: 0-26.2 months).
Immunogenicity
In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 200 mg every three 
weeks, or 10 mg/kg every two or three weeks, 36 (1.8%) of 2,034 evaluable patients tested positive for 

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treatment-emergent antibodies to pembrolizumab, of which 9 (0.4%) patients had neutralizing antibodies 
against pembrolizumab. There was no evidence of an altered pharmacokinetic or safety profile with anti-
pembrolizumab binding or neutralizing antibody development.
Other immune-mediated adverse reactions
The following additional clinically significant, immune-mediated adverse reactions were reported in
less than 1% of patients treated with pembrolizumab in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, 
and KEYNOTE-010: uveitis, myositis, Guillain-Barré syndrome, pancreatitis, encephalitis, sarcoidosis, 
myasthenic syndrome, myelitis, and vasculitis. The following were reported in other clinical studies with 
pembrolizumab or in post-marketing use: myocarditis and sclerosing cholangitis. Cases of these immune-
mediated adverse reactions, some of which were severe, have been reported in clinical trials or in post-
marketing use. Cases of arthritis/arthralgia, hemophagocytic lymphohistiocytosis (HLH) and Vogt-Koyanagi-
Harada syndrome were identified based on post-marketing reports. These side effects were voluntarily reported 
from a group of people of unknown size who received pembrolizumab. It is not possible to estimate the 
frequency of these side effects.
Transplant-related adverse reactions
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with 
pembrolizumab. Treatment with pembrolizumab may increase the risk of rejection in solid organ transplant 
recipients. Consider the benefit of treatment with pembrolizumab versus the risk of possible organ rejection in 
these patients.
Infusion-related reactions
Severe infusion reactions, including hypersensitivity and anaphylaxis, have been reported in 6 (0.2%) of 2799 
patients receiving pembrolizumab in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010. 
For severe infusion reactions, stop infusion and permanently discontinue pembrolizumab. Patients with mild or 
moderate infusion reaction may continue to receive pembrolizumab with close monitoring; premedication with 
antipyretic and antihistamine may be considered. 
Potential for Drug-Drug Interactions
No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab.
Contraindications
None. 
11.2. 3   Risks related to blood draws and saliva collection
No major risks are involved with blood draws. Minor complications including bleeding, pain, and hematoma 
formation at the site of blood draws, vasovagal reactions or infections may rarely occur. There is no risk or 
discomfort associated with saliva collection. 
11. 2. 4   Risks related to CT Scan
CT (computed tomography) uses special x-ray equipment to obtain image data from different angles around the 
body and then uses computer processing of the information to show a cross-section of body tissues and organs. 
Oral and/or intravenous contrast agents will be used and are usually well tolerated. However, some subjects 
will experience allergic reactions to intravenous contrast. To lower the risk of allergic reactions, low allergenic 
contrast agents are administered at NIH clinical center.  In addition, subjects will be advised that approximately 

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2-7% of patients who receive contrast agents will experience a temporary reduction in kidney function lasting 
up to 2 weeks following infusion and that in rare instances, permanent renal damage can result from the use of 
the IV contrasting agent. Therefore, in subjects with impaired kidney function, we will not use intravenous 
contrast. The amount of radiation subjects will receive from the research scans in this study is 3.8 rem of 
radiation annually. All female subjects will receive pregnancy testing prior to radiation exposure.
11. 2. 5
Risks related to pregnancy and nursing mothers
There are no clinical studies in pregnant women, and it is unknown whether ibrutinib, pembrolizumab, or their 
metabolites are excreted in human milk. Men and women of child-bearing potential must use highly effective 
contraceptive (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices 
[IUDs], sexual abstinence, or sterilized partner) protection while on study and for 30 days after the last dose of 
study drug. If a female subject or the partner of a male subject becomes pregnant, the sponsor must be notified. 
Male subjects should refrain from sperm donation.
11. 2. 6 
Risks related to bone marrow biopsy
The anesthetic can cause some temporary stinging and burning. A pulling sensation and discomfort may be felt 
as the marrow is withdrawn. Although rare, there is a potential for bleeding at the site and local infection. 
Bleeding can be stopped by applying local pressure, and infection can be treated with antibiotics.
11.3
Risks in relation to benefit
The benefits to the adult patient could be a reduction or a control of the CLL/SLL resulting in an improved 
quality of life, a decreased susceptibility to infections, and foremost a significant improvement in survival time.  
Potentially, treatment with other therapies could also be avoided or postponed. 
11.4
Informed consent processes and procedures
The investigational nature and research objectives of this trial, the procedure and its attendant risks and 
discomforts will be carefully explained to the subject and a signed informed consent document will be obtained 
prior to entry onto this study.  
At any time during participation in the protocol, should new information become available relating to risks, 
adverse events, or toxicities, this information will be provided orally or in writing to all enrolled or prospective 
patient participants.  Documentation will be provided to the IRB and if necessary the informed consent amended 
to reflect relevant information.
If there is an unexpected enrollment of a research participant for which there is no translated extant IRB 
approved consent document, the principal investigator and/or those authorized to obtain informed consent will 
use the Short Form Oral Consent. 
Refer to Section 11.1.2 for consent process for adults with decisional impairment.
Note: Effective January 21, 2019, a witness to the signature of the written long form research consent at an 
NIH site (whether initially approved by an IRB before or after January 21, 2019) is no longer a requirement.
Consent processes using telephone or telehealth platform

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Participants may be contacted by telephone and or Telehealth (NIH approved platform) to obtain informed 
consent. It may be used for subjects actively participating in the study who may need to be re-consented. The 
telephone consents will be obtained by those investigators designated as authorized to obtain inform consent 
on the Study Personnel page. Telehealth procedure will follow the NIH-approved policy. Procedures for 
obtaining telephone consent are as follows:

The informed consent document will be sent to the patient either by mail (U.S. Postal Service or Fed-Ex), 
fax, or e-mail prior to the phone conversation. If mailed, a pre-addressed return envelope may be included.

A telephone call or telehealth appointment will be scheduled between the participate and designated 
investigator to allow time for the participate to thoroughly read over the consent. The protocol will be 
discussed and explained during the scheduled call or telehealth appointment and any questions will be 
answered. 

If the patient agrees to participate, the patient will print (if email was used to send the consent), sign and 
date the informed consent document with the date of the telephone/telehealth conversation.

The patient is to return the signed document by mail or fax to the investigator. Upon receiving consent, the 
investigator will sign and date the consent with date of receipt of the consent document. This document 
will be designated as both the original and telephone consent.  

A copy of the fully executed document will be returned to the patient by mail or secure email for the 
patient’s record. The signed consent will be sent to medical records to be placed in the patients electronic 
chart.  

The informed consent process will be documented on a CRIS progress note (Progress Note - Documentation 
of Consent) by the investigator.
11.5
Conflict of interest
Merck is providing pembrolizumab for this study to NIH without charge. No NIH investigator involved in this 
study receives any payment or other benefits from Merck. The principal investigator assures that each associate 
investigator listed on the protocol title page received a copy of the NIH’s Guide to preventing conflict of 
interest. No members of the research team reported a potential conflict of interest.  
11.6
Technical Transfer Agreements
The protocol has the following associated CRADA: between NHLBI and Merck, between NHLBI and 
Pharmacyclics, an AbbVie Company, LLC. 
12.0
PHARMACEUTICALS 
12.1
Ibrutinib
Product description: Ibrutinib is commercially available. Note for more detailed and comprehensive 
background information please refer to the ibrutinib Package Insert. Chemical name of ibrutinib is PCI-32765-
00, which is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-piperidinyl]-2-
propen-1-one. PCI-32765-00 is a white to off-white crystalline solid, and given as an oral formulation 
containing micronized PCI-32765-00.
Formulation, Packaging, and Storage: Ibrutinib is provided as a gray, immediate-release hard gelatin capsule 
containing 140 mg of ibrutinib.  The capsules are packaged in blister pack with aluminum lidding foil or opaque 
high-density polyethylene (HDPE) plastic bottles with labels bearing the appropriate label text as required by 
governing regulatory agencies. All study drug will be dispensed in child-resistant packaging. The drug product 
is manufactured for Pharmacyclics LLC, an AbbVie Company, by a contract manufacturer.  All formulation 
excipients are compendial and are commonly used in oral formulations. Each bottle contains 92 capsules.  

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Dosage and Administration: The investigator must ensure that patients receive ibrutinib only from personnel 
who fully understand the procedures for administering the drug.
At any given visit, up to 4-month supply of ibrutinib can be dispensed. In cases where there are patient 
scheduling conflicts, additional doses of ibrutinib may be given to accommodate visits within the window 
specified in the protocol. Drug dispensed will be recorded in ID MRS for drug accountability. Missed or held 
doses will be recorded at every clinic visit. If the patient is taken off from the study, unused ibrutinib capsules 
must be returned to ID MRS for local destruction according to institution’s standard operating procedures. 
Returned capsules must not be re-dispensed.
Ibrutinib 420 mg (3 capsules at 140-mg per capsule) is intended to be administered orally once daily with 8 
ounces (approximately 240 mL) of water (avoid GRAPEFRUIT JUICE and SEVILLE ORANGES due to 
CYP450 3A4 inhibition).  The capsules should be swallowed intact and patients should not attempt to open 
capsules or dissolve them in water.  
If a dose is missed, it can be taken up to 6 hours after the scheduled time with a return to the normal schedule 
the following day. If it has been greater than 6 hours, the dose should not be taken and the patient should take 
the next dose at the scheduled time the next day. The missed dose will not be made up. 
Overdose: Any dose of study drug in excess of that specified in this protocol is considered to be an overdose.  
Signs and symptoms of an overdose that meet any Serious Adverse Event criterion must be reported as a Serious 
Adverse Event in the appropriate time frame and documented as clinical sequelae to an overdose. There is 
Limited data on the effects of ibrutinib overdose. No maximum tolerated dose (MTD) was reached in the Phase 
1 study in which subjects received up to 12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed up to 
single dose of 1680 mg. In a separate study, one healthy subject experienced reversible Grade 4 hepatic enzyme 
increases (AST and ALT) after a dose of 1680 mg. There is no specific antidote to ibrutinib. Subjects who 
ingested more than the recommended dosage should be closely monitored and given appropriate supportive 
treatment. Refer to Section 10.3.1 for further information regarding AE reporting. 
Supply: The drug product ibrutinib is manufactured and supplied by Pharmacyclics LLC, an AbbVie Company.
Shipping:
National Institutes of Health
Investigational Drug Management and Research Section
Clinical Center Pharmacy Department, Room 1C230
10 Center Drive, MSC1196, Building 10
Bethesda, MD 20892-1196
Phone: (301) 496-1031
12.2
Fludarabine:  
Product description: Fludarabine phosphate is commercially available as both a lyophilized powder for 
injection in vials containing 50 mg of fludarabine phosphate with mannitol 50 mg and sodium hydroxide for 
pH adjustment and a solution for injection in 2 mL vials containing 50 mg of fludarabine phosphate (25 mg/mL 

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of 
fludarabine) 
with 
25 
mg/mL 
mannitol 
and 
sodium 
hydroxide 
for 
pH 
adjustment.
Preparation: Fludarabine lyophilized powder for injection should be reconstituted with 2 mL of sterile water 
for injection, up to a concentration of 25 mg/mL. The prescribed dose of fludarabine should be diluted in 100 
mL of either 0.9% sodium chloride or 5% dextrose in water for intravenous administration over 30 minutes.
Storage and Stability: Fludarabine vials should be stored under refrigeration between 2-8 oC (36- 46 
oF).  Reconstituted fludarabine phosphate is chemically and physically stable for 24 hours at room temperature 
or for 48 hours if refrigerated. The manufacturer recommends use of either the reconstituted powder for 
injection or the solution for injection (once diluted for administration) within 8 hours because neither product 
contains an antimicrobial preservative.
Administration: The prescribed dose of fludarabine should be diluted in 100 mL of either 0.9% sodium 
chloride or 5% dextrose in water for intravenous administration over 30 minutes.
Supply: Commercially available.
12.3
Pembrolizumab
Background Information: Note for more detailed and comprehensive background information please refer 
to the Investigator’s Brochure.
Investigational Product Name and Description: Pembrolizumab is a humanized monoclonal antibody that 
blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa 
immunoglobulin with an approximate molecular weight of 149 kDa. 
Preparation: The vials contain 4 mL of sterile solution for IV infusion, 25 mg/mL pembrolizumab, and a 
total of 100 mg protein/vial. Pembrolizumab Solution for Infusion 100 mg/vial is a liquid drug product (DP) 
(manufactured using the fully formulated drug substance with L-histidine as a buffering agent, polysorbate 80 
as a surfactant, and sucrose as a stabilizer/tonicity modifier and water for Injection as Solvent). The DP is 
manufactured using facilities and practices under GMP requirements.
Packaging, and Storage: Pembrolizumab DP is a sterile-filtered liquid and is aseptically filled into single-
use vials. stored under refrigerated conditions at 2°C to 8°C (36°F to 46°F).
Administration: The liquid product is intended for IV administration. The liquid DP can be further diluted 
with normal saline or 5% dextrose in the concentration range of 1 to 10 mg/mL in IV containers made of 
polyvinyl chloride (PVC) or non-PVC material. At the point of use, pembrolizumab DP is diluted with 0.9% 
sodium chloride injection, USP (normal saline) or 5% dextrose injection, USP (5% dextrose) to 1 to 10 
mg/mL before IV administration through an infusion filter. 
Reconstituted vials should be used immediately to prepare the infusion solution in the IV bag, and the 
infusion solution should be administered immediately. If the diluted pembrolizumab solution is not used 
immediately, it may be stored for no more than 24 hours at 2°C to 8°C. This 24-hour hold time from 
reconstitution may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials 
and/or IV bags must be allowed to come to room temperature before to use. 

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Supply: The drug product pembrolizumab is manufactured and supplied by Merck.
Shipping:  
National Institutes of Health
Investigational Drug Management and Research Section
Clinical Center Pharmacy Department, Room 1C230
10 Center Drive, MSC1196, Building 10
Bethesda, MD 20892-1196
12.4
Accountability procedures
Drug accountability records will be maintained for all clinical supplies. All empty and partially used vials and 
clinical trial supplies will be destroyed locally according to the institution’s standard operating procedures for 
drug destruction.  The pharmacy will maintain detailed documentation of the number and identification of vials 
which are destroyed, and copies of these documents will be provided to the sponsor.  Disposition of all unused 
boxes of study drug will be carried out according to instructions provided by the sponsor at the end of the study 
after drug accountability is performed by the study monitor.

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13.0
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young patients with chronic lymphocytic leukemia (CLL) and an adverse biologic profile. Leukemia research 
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Tam CS, O'Brien S, Plunkett W, et al. Long-term results of first salvage treatment in CLL patients 
treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood 2014;124:3059-64.

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Amendment N, July 20, 2022
71
38.
Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in 
fludarabine-refractory chronic lymphocytic leukemia. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2010;28:1749-55.
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chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011;117:3016-24.
40.
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and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic 
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Clinical Oncology 2011;29:3559-66.
41.
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Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the 
European Society for Medical Oncology / ESMO 2011;22 Suppl 6:vi50-4.
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Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during transition to a new treatment 
era: stem cell transplantation or novel agents? Blood 2014;124:3841-9.
43.
Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has 
significant activity in patients with relapsed/refractory B-cell malignancies. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2013;31:88-94.
44.
Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-kappaB signaling and 
reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood 2014;123:3286-95.
45.
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic 
leukemia. N Engl J Med 2013;369:32-42.
46.
Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic 
lymphoid leukemia. N Engl J Med 2014;371:213-23.
47.
O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic 
lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. The 
Lancet Oncology 2014;15:48-58.
48.
Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory 
chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. The Lancet Oncology 
2015;16:169-76.
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Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients 
with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. The lancet oncology 2014;15:1090-
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50.
Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with 
ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood 2015;126:842-50.
51.
Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with 
chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood 2015;125:2915-22.
52.
Cramer P, Chanan-Khan A, Demirkan F, et al. Ibrutinib combined with bendamustine/rituximab in 
previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from 
a randomized, double-blind, phase 3 study. Haematologica 2015;100:55-6.
53.
Kim E, Werner L, Keating MJ, et al. Addition of rituximab abrogates ibrutinib-induced lymphocytosis 
and promotes more rapid decrease in absolute lymphocyte counts in patients with relapsed chronic lymphocytic 
leukemia. Blood 2014;124.
54.
Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, 
for relapsed/refractory chronic lymphocytic leukemia. Blood 2014;123:3390-7.
55.
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic 
leukemia. N Engl J Med 2014;370:997-1007.

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Amendment N, July 20, 2022
72
56.
Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves 
antitumor activity while sparing platelets. Nat Med 2013;19:202-8.
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lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): High complete-response rate and 
durable disease control. Journal of Clinical Oncology 2014;32.
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patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497-506.
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Lymphocytic Leukemia. N Engl J Med 2015;373:2425-37.
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Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton's tyrosine kinase 
inhibitor ibrutinib. N Engl J Med 2014;370:2286-94.
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Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med 
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Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with 
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Trial E2997. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2007;25:793-8.

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Amendment N, July 20, 2022
73
74.
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in 
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75.
Geller NL. Advances in clinical trial biostatistics. New York: Marcel Dekker; 2004.

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Amendment N, July 20, 2022
74
APPENDIX A:  Schedule of Events 
Study Day/NAME: 
Scre
enin
g/B
aseli
ne
Pre 
C-3 
& -1
C-2 (28-day)
C1 to 17
(21-day)
After cycle 17
(every 4 
months)@
Response at 6 
months (from 
cycle 1)
Response  at 
1 year (from 
cycle 1) and 
annually
At 
progression 
Days (Plus/Minus)
N/A
±5
±5
±5
±14
±30
±30
N/A
Day of the cycle
N/A
N/A
D1
D2
D3
D4
D5
D14
D21
D1
N/A
N/A
N/A
N/A
NIH visit
[R]
X
X
X
X
X
X
X
X
X
X
 [R]
Clinical
 
 
 
 
Consent
 
X 
 
 
 
History, ECOG PS
X
X
X
X
X
X
X
[R]
Physical Exam 
X
X
X
X
X
X
X
[R] 
Medication Review
X
X
X
X
X
X
X
[R]
Specific Labs/Other Tests
 
 
 
 
HLA Typing*, Saliva
X
CBC with Differential
X
X
X
[X]
X
X
X
X
[R]
Acute Care & Mineral Panels
X
X
X
X
X
X
X
[R]
Tot. protein, CK, Uric Acid, LDH 
X
[R]
X
X
X
X
X
[R]
Hepatic Panel
X
X
X
X
X
X
X
[R] 
Reticulocyte Count
X
[R]
X
X
X
X
X
[R]
PT, PTT
X
X
X
X
X
X
X
[R]
SPEP with IFE
 
 
[R]
SFL, qIG
 
 
X
X
[R]
CRP
[R]
β2  microglobulin
X
[R]
X
X
X
X
X
[R]
Haptoglobin, DAT
X
[R]
X
X
X
X
X
[R]
Iron panel, folate, B12 level
X
 
 
Thyroid function panel
X
X
[R]
Viral Studies (HIV, hepatitis) 
X
 
 
 
EBV, CMV PCR
[R]
BKT and PLCg2 mutation analysis
[R]
Pregnancy test
X
X
X
X
X
X
X
[R]
TBNK
X
X
X*
X
X
[R]
IGHV mutation analysis
[X]
[R]
CLL/ FISH (w/in 3 mo of starting)
[X]
[R]
Karyotype (w/in 3 mo of starting)
[X]
Flow CLL (w/in 3 mo of starting)
X
X
X
[R]
CT Neck, CAP (w/in 3 mo of starting)
[X]
X#*
[R]
 [R]
[R]

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Amendment N, July 20, 2022
75
Footnotes for Schedule of Events:
* 
Prior to cycle 1 only. No need test before other cycles.
**
Can be CT or PET/CT of neck, chest, abdomen, and pelvis at progression
*** Up to 3 lymph node biopsy can be performed in consented patients.
#
Patient may choose to waive CT scan prior to pembrolizumab.
## Research blood is mandatory at cycle -3, -2, -1, 1, and at response assessments. Research blood is optional for other timepoints. 
@ Patients with travel hardships can be followed every 8 months and draw an interim CBC with differential to substitute a missed visit and evaluations. Outside 
lab results are accepted for the interim lab.
[R] Optional, at discretion of clinical team
X 
Will be done on study
[X] Outside labs are accepted
Bone Marrow (w/in 3 mo of starting)
[X]
[R]
-[R]
[R]
EKG (w/in 3 mo of starting, then if 
medically indicated)
X
 
 
Research Samples
 
 
 
 
Lymphapheresis
[R]
[R]
[R]
[R]
Lymph node biopsy***
[R]
[R]
[R]
[R] 
Research blood##
X
X
X
X/[R]
[R]
X
 [R]
[R]

17-H-0118
Adrian Wiestner, M.D., Ph.D. 
Amendment N, July 20, 2022
76
Appendix B.
Inhibitors and Inducers of CYP3A
Inhibitors and inducers of CYP3A enzymes are defined as follows. Further information can be found at the 
following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/.
Inhibitors of CYP3A
Inducers of CYP3A
Strong inhibitors:
carbamazepine
boceprevir
barbiturates
clarithromycin
efavirenz
cobicistat
glucocorticoids
indinavir
modafinil
itraconazole
nevirapine
ketoconazole
oxcarbazepine
mibefradil
phenobarbital
nefazodone
phenytoin
nelfinavir
pioglitazone
posaconazolea
rifabutin
ritonavir
rifampin
saquinavir
St. John’s Wort
suboxone
troglitazone
telaprevir
telithromycin
troleandomycin
Moderate inhibitors:
amiodarone
amprenavir
aprepitant
atazanavir
ciprofloxacin
crizotinib
darunavir
diltiazem 
dronedarone
erythromycin
fluconazole
fosamprenavir
grapefruit juice
imatinib
Seville orange juice
verapamil
voriconazolea 
Weak inhibitors:
cimetidine
fluvoxamine
All other inhibitors:
chloramphenicol
delaviridine 
diethyl-dithiocarbamate
gestodene
mifepristone
norfloxacin
norfluoxetine
star fruit
a.
Classification based on internal data.

17-H-0118
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Amendment N, July 20, 2022
77
Appendix C.
Child-Pugh Score for Subjects with Liver Impairment
Measure
1 point
2 points
3 points
Total bilirubin, μmol/L (mg/dL)
<34 (<2)
34-50 (2-3)
>50 (>3)
Serum albumin, g/L (g/dL)
>35 (>3.5)
28-35 (2.8-3.5)
<28 (<2.8)
PT/INR
<1.7
1.71-2.30
>2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed 
with medication)
Grade III-IV 
(or refractory)
Points
Class
5-6
A
7-9
B
10-15
C
Source: 
1.
Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964;50-64.  
2.
Pugh RN, Murray-Lyon IM, Dawson L, et al . Transection of the oesophagus for bleeding esophageal 
varices.  The British journal of surgery, 1973;60:646-9.