A Pilot Phase II Study Using Ibrutinib and Short-Course Fludarabine in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

15-H-0172
Inhye Ahn, M.D.
March 26, 2019 (Amendment L)
1 
CLINICAL RESEARCH PROJECT 
Protocol #: 15-H-0172 
Drug Names: Ibrutinib and Fludarabine 
IND: Exempt 
Title: A Pilot Phase II Study of Ibrutinib and Short-Course Fludarabine in Previously Untreated Patients with 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) 
Short Title: Ibrutinib and fludarabine in untreated CLL 
Keywords: Ibrutinib, Fludarabine, BTK Inhibitor, T-cell Modulation, CLL, SLL 
Principal Investigator: 
Inhye Ahn, M.D., NHLBI (E)* 
Accountable and Medically Responsible Investigator: 
Adrian Wiestner, M.D., Ph.D., HB, NHLBI (E)*  
Associate Investigators:  
Raul Braylan, M.D., DLM, CC, NIH (E) 
Katherine R. Calvo, M.D., Ph.D, DLM, CC, NIH (E) 
Erika Gaglione, BA, HB, NHLBI (C)
Thomas Hughes, Pharm.D., CC (E)  
Jennifer Lotter, PA (E)* 
Irina Maric, M.D., DLM, CC, NIH (E) 
Gerald Marti, M.D., Ph.D., NHLBI (V)* 
Pia Nierman, RN., HB, NHLBI (E) 
Christopher Pleyer, M.D., HB, NHLBI (E)* 
Susan Soto, M.S.N., RN., HB, NHLBI (E)  
Maryalice Stetler-Stevenson, M.D., CCR (E) 
Clare Sun, M.D., HB, NHLBI (E)* 
Jeanine Superata, FNP, HB, NHLBI (E)* 
Xin Tian, Ph.D., Biostatistician, OBR, NHLBI (E)  
Janet Valdez, PA-C, HB, NHLBI (E)*   
Constance Yuan, M.D., CCR (E) 
*Indicates who may obtain informed consent.
Company Providing Investigational Drug:  Pharmacyclics, an AbbVie Company 
Subjects of Study: 
Number  
Sex 
Age-range 
32 
M/F 
> 18
Ionizing Radiation for Research: 
Yes 
Off-Site Project:  
No 
Multi-center trial: 
No 
DSMB Involvement: 
Yes 
NCT02514083

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
2 
PRECIS 
 
Chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL) are tumors of B cells that 
often affect elderly patients. While the cause of CLL is still unclear, studies have indicated critical factors 
required for the tumor cells. First, CLL cells grow and survive because they receive signals through the B-cell 
receptor (BCR); and second, CLL cells benefit from interactions with other cells, especially T cells.  
 
The stimulation through the BCR can be reduced with ibrutinib, which is an oral drug that selectively inhibits 
Bruton’s tyrosine kinase (BTK). 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 patients with 17p 
deletion and for those who had at least one prior therapy. However, single-agent ibrutinib has limitations; the 
drug does not eliminate all the tumor cells, and, with time, the tumor cells may become resistant. Therefore, 
combination of ibrutinib with other drugs could be beneficial. Here we chose fludarabine because it 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. With this approach we hope to restore healthier immune system. 
 
This study will investigate the safety and efficacy of ibrutinib combined with fludarabine. This protocol is 
intended for previously untreated CLL patients. Ibrutinib will be given daily until disease progression or 
intolerable side effects occur. Fludarabine will be given only in cycles 3 and 4.  
 

15-H-0172
Inhye Ahn, M.D.
March 26, 2019 (Amendment L)
3 
1.0 
OBJECTIVES ................................................................................................................................................. 6 
1.1 
PRIMARY OBJECTIVE ................................................................................................................................................. 6 
1.2 
SECONDARY OBJECTIVES ............................................................................................................................................ 6 
2.0 
BACKGROUND AND SCIENTIFIC JUSTIFICATION ............................................................................... 6 
2.1 
PATHOPHYSIOLOGY .................................................................................................................................................. 6 
2.2 
EPIDEMIOLOGY AND CLINICAL COURSE OF CLL ............................................................................................................... 7 
2.3 
DIAGNOSTIC AND PROGNOSTIC CATEGORIES OF CLL/SLL ................................................................................................. 7 
2.4 
INDICATIONS FOR CLL TREATMENT ............................................................................................................................. 8 
2.5 
CURRENT TREATMENT OPTIONS FOR CLL/SLL ............................................................................................................... 9 
2.5.1 
Watchful Waiting ........................................................................................................................................... 9 
2.5.2 
First-line Chemotherapy/Immunotherapy/Chemoimmunotherapy ............................................................... 9 
2.5.3 
Complications of Chemoimmunotherapy ..................................................................................................... 10 
2.5.4 
Relapsed or Refractory CLL ........................................................................................................................... 10 
2.5.5 
Stem Cell Transplantation: ........................................................................................................................... 11 
2.5.6 
Targeted Tyrosine Kinase Inhibitors ............................................................................................................. 11 
2.5.7 
Other Options ............................................................................................................................................... 11 
2.6 
IBRUTINIB ............................................................................................................................................................ 12 
2.6.1 
Mechanism of Action, Distribution, Metabolism and Clearance48 ............................................................... 12 
2.6.2 
Clinical Experience in CLL .............................................................................................................................. 12 
2.7 
SUMMARY OF CLINICAL SAFETY ................................................................................................................................ 14 
2.7.1 
Clinical and scientific justification for protocol design ................................................................................. 15 
3.0 
STUDY DESIGN ........................................................................................................................................... 16 
4.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ................................................................................ 17 
4.1 
INCLUSION CRITERIA ............................................................................................................................................... 17 
4.2 
EXCLUSION CRITERIA .............................................................................................................................................. 17 
5.0 
TREATMENT PLAN .................................................................................................................................... 18 
5.1 
DRUG ADMINISTRATION .......................................................................................................................................... 18 
5.2 
THERAPY SCHEDULE: ........................................................................................................................................ 19 
5.3 
PROPHYLACTIC MEDICATIONS: ................................................................................................................................. 19 
5.4 
HOLDING AND DOSE ADJUSTMENTS OF STUDY DRUG ADMINISTRATION IN THE CASE OF TREATMENT RELATED TOXICITY ............... 19 
5.4.1 
Cytopenia: .................................................................................................................................................... 19 
5.4.2 
Atrial fibrillation: ...................................................................................................................................... 20 
5.4.3 
Non-hematologic toxicities: ......................................................................................................................... 20 
5.4.4 
Dose modification for hepatic impaired subjects: ........................................................................................ 20 
5.5 
HOLDING OF STUDY DRUG ADMINISTRATION .............................................................................................................. 21 
5.5.1 
Ibrutinib and Surgical Procedures: ............................................................................................................... 21 
5.5.2 
Medically Necessary Conditions to Hold Study Drugs: ................................................................................. 21 
5.5.3 
Permanent discontinuation of study drug administration in case of treatment related adverse events: .... 21 
5.6 
SUPPORTIVE CARE (NON-INVESTIGATIONAL) ............................................................................................................... 21 
5.6.1 
Blood Products ............................................................................................................................................. 21 
5.6.2 
Growth Factors ............................................................................................................................................ 21 
5.6.4 
PCP prophylaxis .......................................................................................................................................... 21 
5.6.5 
Anti-viral prophylaxis .................................................................................................................................. 22 
5.7 
PERMITTED AND NON PERMITTED CONCOMITANT MEDICATIONS (INVESTIGATORS BROCHURE) ........................................... 22 

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Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
4 
5.7.1   
Guideline for Use of CYP Inhibiting Drugs ................................................................................................ 22 
5.7.3  
Concomitant Use of Antiplatelet Agents and Anticoagulants.................................................................. 22 
5.8 
SPECIAL INSTRUCTIONS FOR PATIENTS ........................................................................................................................ 23 
5.8.1 
Immunizations: ............................................................................................................................................. 23 
5.8.2 
Birth control: ................................................................................................................................................ 23 
5.9 
PROHIBITED CONCOMITANT MEDICATIONS ................................................................................................................ 23 
6.0 
CLINICAL MONITORING ......................................................................................................................... 23 
6.1 
STUDY EVALUATIONS: SCREENING AND BASELINE (SEE SCHEDULE OF EVENTS APPENDIX A) .................................................. 23 
Screening evaluation will include the following (also see schedule of events). ......................................................... 23 
Baseline evaluation will include the following (also see schedule of events). ........................................................... 24 
6.2 
ON THERAPY EVALUATIONS (SEE SCHEDULE OF EVENTS APPENDIX A) ............................................................................... 25 
6.3 
RESPONSE ASSESSMENT (SEE SCHEDULE OF EVENTS APPENDIX A) (+/- 30-DAY WINDOW) ................................................... 26 
6.4 
AT PROGRESSION EVALUATION (SEE SCHEDULE OF EVENTS APPENDIX A) ........................................................................... 27 
7.0 
CRITERIA FOR RESPONSE ...................................................................................................................... 27 
8.0 
ANCILLARY LABORATORY RESEARCH STUDIES ............................................................................. 28 
8.1 
COLLECTION OF SAMPLES ........................................................................................................................................ 28 
8.2 
INTENDED USE ...................................................................................................................................................... 29 
8.3 
STORAGE, TRACKING AND DISPOSITION OF SAMPLES AND DATA ....................................................................................... 29 
9.0 
BIOSTATISTICAL CONSIDERATIONS ................................................................................................... 30 
9.1 
PRIMARY ENDPOINT: .............................................................................................................................................. 30 
9.2 
SECONDARY ENDPOINTS: ......................................................................................................................................... 30 
9.3 
SAMPLE SIZE ......................................................................................................................................................... 30 
9.4 
STATISTICAL METHODS ........................................................................................................................................... 31 
9.5 
STUDY STOPPING RULES ......................................................................................................................................... 31 
9.6 
STOPPING RULE FOR MORTALITY: ............................................................................................................................. 32 
9.7 
OFF STUDY CRITERIA (FOR SUBJECT PARTICIPATION) ..................................................................................................... 33 
10.0 DATA AND SAFETY MONITORING ........................................................................................................ 33 
10.1 
ASSESSMENT OF SAFETY .......................................................................................................................................... 34 
10.1.1 
Severity .................................................................................................................................................... 36 
10.1.2 
Pregnancy ................................................................................................................................................ 36 
10.1.3 
AE and SAE causality assessments ........................................................................................................... 37 
10.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS ADVERSE EVENTS .................................................................. 37 
10.3 
NHLBI-IRB AND CD REPORTING .............................................................................................................................. 37 
10.3.1 
Serious Events .......................................................................................................................................... 37 
10.3.2 
Non-serious Events ................................................................................................................................... 38 
10.3.3 
Deaths ...................................................................................................................................................... 38 
10.4 
REPORTS AT THE TIME OF CONTINUING IRB REVIEW: .................................................................................................... 38 
10.4.1 
Reporting Period for AEs .......................................................................................................................... 38 
10.4.2 
Reporting Period and Reporting Requirements for SAEs ......................................................................... 39 
10.4.3 
Adverse Events of Special Interest (AESI) ................................................................................................. 39 
10.5 
DATA MANAGEMENT .............................................................................................................................................. 39 
10.6 
PROTOCOL AMENDMENTS ....................................................................................................................................... 40 
10.7 
PROTOCOL MONITORING ........................................................................................................................................ 40 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
5 
11.0 HUMAN SUBJECT PROTECTION ............................................................................................................ 41 
11.1 
RATIONALE FOR SUBJECT SELECTION ......................................................................................................................... 41 
11.1.1 
Predicted distribution by gender, age and race: ..................................................................................... 41 
11.1.2 
Special Populations: ................................................................................................................................. 41 
11.2 
RISKS AND DISCOMFORTS ........................................................................................................................................ 42 
11.2.1 
Risks related to Ibrutinib .......................................................................................................................... 42 
11.2.2 Risks related to blood draws: ......................................................................................................................... 45 
11.2.3 
Risks related to CT Scan: ......................................................................................................................... 45 
11.2.4 Related to pregnancy and nursing mothers: .................................................................................................. 46 
11.2.5 Related to central line placement ................................................................................................................... 46 
11.2.6 Risks related to bone marrow biopsy: ............................................................................................................ 46 
11.2.7 Risks related to transfusions:.......................................................................................................................... 46 
11.3 
RISKS IN RELATION TO BENEFIT................................................................................................................................. 46 
11.4 
INFORMED CONSENT PROCESSES AND PROCEDURES ...................................................................................................... 46 
11.5 
CONFLICT OF INTEREST ........................................................................................................................................... 47 
11.6 
TECHNICAL TRANSFER AGREEMENTS ......................................................................................................................... 47 
12.0 PHARMACEUTICALS ................................................................................................................................ 47 
12.1 
IBRUTINIB48 .......................................................................................................................................................... 47 
12.2 
FLUDARABINE: ...................................................................................................................................................... 48 
12.3 
OFF-LABEL USE OF DRUGS ...................................................................................................................................... 49 
12.4 
ACCOUNTABILITY PROCEDURES ................................................................................................................................ 49 
13.0 REFERENCES .............................................................................................................................................. 50 
 
APPENDIX A:  Schedule of Events  
APPENDIX B:  NHLBI HEMATOLOGY BRANCH LABORATORY RESEARCH STUDIES 
APPENDIX C: NIH INFORMATION SHEET ON STAFF RESEARCH PARTICIPATION (APRIL 2016) 
 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
6 
1.0 
OBJECTIVES  
1.1 
Primary objective 
• 
To test the safety and efficacy of ibrutinib-based therapy combined with a short-course fludarabine in 
previously untreated patients with chronic lymphocytic leukemia (CLL) and/or small lymphocytic 
leukemia (SLL) 
 
1.2 
Secondary objectives  
• 
Duration of response  
• 
Best response 
• 
Minimal residual disease status 
• 
To explore the biologic effects on B- and T-cell subsets and function 
• 
To explore the lack of clinical response  
 
2.0 
BACKGROUND AND SCIENTIFIC JUSTIFICATION  
 
Chronic Lymphocytic Leukemia (CLL) and/or small lymphocytic lymphoma (SLL) 
The World Health Organization classification of hematopoietic neoplasms describes CLL as a leukemic, 
lymphocytic lymphoma, being only distinguishable from SLL by its leukemic appearance.1 In the National 
Cancer Institute-sponsored Working Group (NCI-WG) guidelines, the diagnosis of CLL requires the presence 
of at least 5 x 109 clonal B lymphocytes/L (5000/µL) in the peripheral blood.2 The definition of SLL requires 
the presence of lymphadenopathy and/or splenomegaly. Clonal B lymphocytes in the peripheral blood should 
not exceed 5 x 109/L and the diagnosis should be confirmed by histopathologic evaluation of a lymph node 
biopsy when possible.3 
 
CLL/SLL cells coexpress the T-cell antigen CD5 and B-cell surface antigens CD19, CD20 and CD23. The 
levels of surface immunoglobulin, CD20, and CD79b are characteristically low compared with those found on 
normal B cells. Each clone of leukemia cells is restricted to express either kappa or lambda immunoglobulin 
light chains.3  
 
For the purposes of this study, the term “CLL” will encompass both CLL and SLL. 
 
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 (SIg) 
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 cascade leads to recruitment and activation of the spleen tyrosine 
kinase (SYK),4 and downstream activation of Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase 
(PI3K).5 Therefore, inhibition of BCR signaling is an important therapeutic target for CLL. 
 
Another key component of CLL pathogenesis is bidirectional interactions between tumor cells and 
microenvironment. First, tumor microenvironment has a stimulatory role and is critical for CLL cell survival. 
CLL cells cultured in vitro undergo apoptosis, but can be rescued by co-culturing them with stromal cells or by 
adding soluble factors.6,7 In patients, T and CLL cells aggregate to form ‘proliferation centers’ within bone 
marrow and LN, and these rallied cells form immune synapses.8 The crosstalk between T and CLL cells 
stimulates survival of leukemic cells, and promotes resistance to apoptosis through CD40 ligand.9,10 Second, T 
cells in CLL are functionally8 and phenotypically11 defective, allowing malignant B cells to escape immune 
surveillance. These “pseudo-exhausted” T cells receive inhibitory signals from CLL, such as CD200, and PD-
L1.8,12 Taken together, simultaneous targeting of tumor microenvironment and BCR pathway can be a 
promising therapeutic strategy in CLL.  

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
7 
2.2 
Epidemiology and clinical course of CLL 
CLL is the most common leukemia of adults in Western countries with an annual incidence of 2–4.5 per 100,000 
in the general population. Based on 1995-2011 North American Association of Central Cancer Registries 
(NAACCR), 14,620 men and women (8,140 men and 6,480 women) were estimated to be newly diagnosed 
with CLL in 2015.13 CLL affects males more frequently than females, and is a disease of older individuals 
(median age 73.0 years for Caucasian).14 The highest rates of incidence are seen in Caucasians followed by 
African Americans. Lower rates of incidence are seen in Asian and Hispanic populations.  
 
Complications of CLL usually arise from progressive disease. These complications are, but are not limited to, 
infection, hematologic abnormalities, immunologic phenomena, secondary malignancy, and disease 
transformation. Up to 70% of patients with CLL will develop infections, which accounts for more than half of 
deaths in CLL.15 Hematologic abnormalities include autoimmune hemolytic anemia (37%), pure red cell aplasia 
(6%), and immune mediated thrombocytopenia (2-4%).15 Secondary cancers are noted in about 11% and include 
acute myeloid leukemia and solid tumors. Disease transformation into other lymphomas occurs in 
approximately 5%, and includes diffuse large B cell lymphoma and Hodgkin’s lymphoma.16 
 
2.3 
Diagnostic and prognostic categories of CLL/SLL  
Diagnosis of CLL is based on complete blood count (CBC) with differential, flow cytometry of peripheral blood 
(to determine the immunophenotype of circulating lymphocytes), and examination of peripheral blood smear. 
According to the 2008 update of the NCI-WG diagnosis and treatment of CLL, following two criteria must be 
met:2   
 
• 
Absolute B lymphocyte count in peripheral blood ≥ 5000/μL (5 x 109/L), with morphologically mature-
appearing small lymphocytes  
• 
Clonality of circulating B lymphocytes defined by peripheral blood flow cytometry. A majority of the 
population should express the following pattern: low levels of surface Ig with either κ or λ (but not both) 
light chains; expression of B-cell associated antigens (CD19, CD20, and CD23); and expression of the T-
cell associated antigen (CD5).  
 
Diagnosis of SLL requires the presence of lymphadenopathy and/or splenomegaly confirmed by histopathologic 
evaluation of LN through biopsy when possible, while peripheral blood B lymphocytes not exceeding 5 x 109/L.  
 
There are two prognostic staging systems in CLL called Rai and Binet. Rai staging system is based on gradual 
and progressive increase in leukemic cell burden - starting from blood and bone marrow, progressively 
involving lymph nodes, and followed by spleen and liver involvement. This will lead to eventual compromise 
of bone marrow function (Table 1). 
 
Table 1:  Rai staging system17 
Stage 
Risk 
Manifestations 
Median survival 
(months) 
0 
Low 
Blood and marrow lymphocytosis 
120 
I 
Intermediate 
Lymphocytosis and adenopathy  
108 
II 
Intermediate 
Lymphocytosis and adenopathy  
94 
III 
High 
Lymphocytosis + anemia (Hb < 11g/dL) 
60 
IV 
High 
Lymphocytosis + thrombocytopenia (Plt < 100K/µL) 
60 
 
  
 
Rai staging system was designed to provide prognostic information, and is of great value in stratifying patients 
with survival curves corresponding to the Rai low-, intermediate-, and high-risk groups, respectively. However, 
this risk stratification system has a limitation in underestimating the risk of progression in subsets of early stage 
patients. For this reason, other prognostic markers, such as immunoglobulin variable heavy chain (IGHV) 
genes, ξ (zeta)-chain associated protein 70 (ZAP-70), and CD38, have been used to identify patient subsets with 
aggressive clinical phenotype. IGHV gene is defined as mutated when there is a greater than 2% difference in 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
8 
nucleotide sequence compared to germline DNA.18 Unmutated IGHV gene status is associated with shorter 
survival and the higher risk of relapse after treatment, including hematopoietic stem cell transplantation.19 ZAP-
70 is a tyrosine kinase normally expressed by NK and T cells, but not in normal B cells. A subset of CLL 
patients express ZAP-70, which is strongly associated with unmutated IGHV status and correlated to poor 
prognosis.20 
 
Genetic abnormalities are another important prognostic marker (Table 2). Development of fluorescence in situ 
hybridization (FISH) in the late 1980s and early 1990s allowed a more sensitive detection of chromosomal 
abnormalities. Using the FISH testing in interphase cells, Döhner et al. identified that deletion 13q14 was the 
most common isolated chromosomal abnormality in CLL (64%).21 Deletion 13q14 is currently believed to be 
a primary event in CLL, supported by its presence in clonality, and, at many times, as the sole abnormality. The 
prognosis of patients with deletion 13q14 appears to be better than, if not similar to, that of patients with a 
normal karyotype.21 Trisomy 12 is thought to confer poor prognosis, and is associated with an atypical 
morphology and immunophenotype, high proliferation rate, and advanced clinical stages. Trisomy 12 is 
typically found as a minority of tumor cells or as a subclone, and may be a secondary abnormality in CLL.21  
 
Table 2: Cytogenetic Abnormalities in CLL21 
Chromosome 
Median OS (months) 
Median time to first 
treatment (months) 
Deletion 17p13 
32 
9 
Deletion 11q22-23 
79 
13 
Trisomy 12 
114 
49 
Normal 
111 
33 
Deletion 13q14 
133 
92 
 
Deletion 17p is found in 7-10% of newly diagnosed CLL and is a predictor of poor prognosis among patients 
requiring therapy. Using karyotype banding, Giesler et al. reported deletion 17p to be associated with poor 
survival, and as the only genetic abnormality with an independent prognostic value.22 Deletions 11q, seen in 
17-20% of patients, is associated with certain clinical phenotypes, such as extensive adenopathy, progressive 
disease and shorter survival in patients under age 55.21 Ataxia telangiectasia mutated (ATM) gene is mapped at 
chromosome 11q, and its loss or mutation involving both alleles has been associated with poor overall survival 
in patients, and impaired cellular response to irradiation as well cytotoxic agents in vitro.23 However, the poor 
prognosis of 11q deletion may be overcome with the use of fludarabine, cyclophosphamide, and rituximab.24 
The prognostic impact of 12q trisomy is controversial with conflicting evidences. For instance, some studies 
have demonstrated advanced disease and higher proliferative activity in patients with trisomy 12, while others 
have demonstrated similar survival to that of normal karyotype.25 Deletion 13q, present in 45-55% of patients, 
appears to be associated with a favorable outcome.21 It is often associated with inactivation of RB1 gene,26 and 
its minimal deleted region is also suspected to harbor non-coding genes with a tumor suppressor role.  
 
Other prognostic markers, such as lymphocyte doubling time (LDT), bone marrow histologic pattern, and β2 
microglobulin (B2M), are useful as an adjunct to genetic abnormalities. Actual or projected LDT can provide 
an estimation of disease kinetics, and its value less than 12 months in untreated patients predicts progressive 
disease course.27 The pattern of lymphocyte infiltration in the bone marrow can be correlated to a progressive 
clinical course (diffuse pattern) versus an indolent one (interstitial and/or nodular pattern).28 Finally, the B2M 
levels correlate with disease stage and tumor burden in CLL.29 
 
2.4 
Indications for CLL Treatment 
Newly diagnosed patients with asymptomatic early-stage disease (Rai 0, Binet A) should be monitored without 
therapy unless they have evidence of disease progression.30 Patients with intermediate to high Rai stages (3 and 
4) or Binet stages (B and C) usually benefit from treatment. 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
9 
According to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL), active disease should 
meet one of the following criteria.3 
• 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 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 30 x 109/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 
(eg, 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:  
a. Unintentional weight loss of 10% or more within the previous 6 months;  
b. Significant fatigue (i.e., ECOG PS 2 or worse; inability to work or perform usual activities);  
c. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of infection; or  
d. Night sweats for more than 1 month without evidence of infection. 
  
2.5 
Current Treatment options for CLL/SLL 
 
2.5.1 
Watchful Waiting 
Immediate treatment is recommended in patients with advanced-stage disease, high tumor burden, and 
severe disease-related "B" symptoms. Otherwise, a period of observation is recommended. Asymptomatic 
early-stage disease should be monitored until disease progression.3 During the observation period, patients 
are periodically monitored with blood counts and assessed for the evidence of progressive disease through 
monitoring of symptoms and physical exam.  
 
2.5.2 
First-line Chemotherapy/Immunotherapy/Chemoimmunotherapy   
 
Monotherapy: 
Monotherapy with alkylating agents has served as an initial frontline treatment strategy for CLL. 
Chlorambucil, which has been considered as the gold standard for CLL for several decades, still remains 
to be an appropriate option for unfit elderly patients.30 Bendamustine is also approved by the U.S. Food and 
Drug Administration (FDA) in 2008 for the treatment of CLL. When chlorambucil and bendamustine were 
compared in previously untreated CLL patients, higher overall response rate (ORR) was achieved with 
bendamustine (68%) than chlorambucil (48%).31  
 
Aside from alkylating agents, purine analogues such as fludarabine, pentostatin and cladribine have been 
used as monotherapies in CLL. Among those, fludarabine is the best-studied compound with a superior 
overall response as a monotherapy compared to other alkylating agents.32  
 
Immunotherapy: 
The advent of monoclonal antibodies opened the era of targeted therapy for hematologic malignancies. 
Rituximab was the first monoclonal antibody targeting CD20, which was initially used as a monotherapy 
demonstrated improved progression-free survival (PFS) in a consolidation setting (estimated 5-year PFS 
73%).33 The addition of anti-CD20 monoclonal antibodies to chemotherapy (referred as 
chemoimmunotherapy) has proven to be very efficacious in CLL and will be discussed below.  
 
Chemoimmunotherapy: 

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Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
10
Alkylating agents, purine analogues and monoclonal antibodies have different mechanisms of action and 
partially non-overlapping toxicity profiles. When combined together, the regimen led to improved 
responses in CLL. For instance, the combination of fludarabine, cyclophosphamide, and rituximab (FCR) 
resulted in an ORR of 90% (complete response (CR) in 44%, partial response (PR) in 46%).34  
Bendamustine combined with rituximab (BR) also has as impressive activities as FCR. In previously 
untreated CLL, BR led to ORR of 88% (CR in 23%, PR in 65%) and 91% survival after a median 
observation time of 27 months.35 Efficacy and safety of BR and FCR were directly compared in German 
CLL study group, which showed identical ORR of two arms (97.8% in both arms).36 Depth of response was 
higher in FCR (CR in 47.4%) than BR (CR in 38.1%), as well as PFS and event-free survival. However, 
these differences did not translate into survival (OS 94.2% in FCR vs. 95.8% in BR at 2 years) due to 
increase toxicity with FCR.  
 
Several other chemoimmunotherapy regimens have been investigated, which include cladribine plus 
rituximab, methylprednisolone plus rituximab, fludarabine plus alemtuzumab, and fludarabine, 
cyclophosphamide plus alemtuzumab. None of these regimens resulted in efficacy comparable to FCR.37 
 
Geode et al. studied a third generation anti-CD20 monoclonal antibody called obinutuzumab in 
combination with chlorambucil for previously untreated CLL patients.38 As expected, obinutuzumab and 
chlorambucil had a higher efficacy than chlorambucil alone, with median PFS of 27 vs. 11 months, 
respectively. Obinutuzumab gained FDA approval to be used in combination with chlorambucil in 2013. 
 
2.5.3 
Complications of Chemoimmunotherapy 
Major limitations of highly active chemoimmunotherapy in CLL - most notably, the FCR regimen - are the 
durability of remission and toxicities. Long-term follow up of patients treated with front-line FCR revealed 
only one third remained in remission while approximately half of them had refractory or relapsing disease.39 
As for toxicities, more than 90% of patients treated with FCR and 78.5% treated with BR experienced 
moderate to severe adverse events (CTCAE grade 3 to 5).36  Hematologic toxicities were more frequent in 
the FCR arm (90.0% vs. 66.9%), leading to higher rates of severe neutropenia (81.7%) and severe infections 
(39.0%) with the FCR arm. Treatment related mortality occurred in 3.9% in the FCR and 2.1% in the BR 
arm. 36 Monoclonal antibodies also add infusional toxicities as seen in rituximab and obinutuzumab. 
Toxicities of chemoimmunotherapy can linger or present in a delayed manner. For example, 20% of patients 
treated with fludarabine and other alkylators were reported to experience persistent cytopenia.39 Intergroup 
study E2997 reported 5% incidence of myeloid neoplasia 6 years after fludarabine and cyclophosphamide 
therapy31; the adjusted incidence for myeloid neoplasia rate at 8 years was 8%.  
 
2.5.4 
Relapsed or Refractory CLL 
There is no standard regimen for patients who has relapsed or refractory CLL. Treatment for this population 
should be individualized based on host and biological factors, including fitness of a patient, comorbidities, 
disease burden (i.e., bulky or non-bulky), and FISH cytogenetics (i.e., deletion 17p).32 
 
Treatment options for relapsed or refractory CLL encompass aforementioned front-line regimens. In a 
phase II trial of FCR in 284 patients with previously treated CLL (19% were fludarabine-refractory and 
35% were rituximab-refractory), ORR was 74 % and median OS was 47 months.40 Presence of fludarabine-
refractory disease, deletion 17p, or more than 3 prior treatments predicted shorter survival in subgroup 
analysis. Another option is BR, which resulted in ORR of 59% in a multicenter phase II trial of 78 relapsed 
and/or refractory CLL.41 However, the duration of response is usually short-lived in this population (median 
duration of response: 15 months).41  
Ofatumumab is a second-generation anti-CD20 antibody being used for relapsed/refractory disease. A 
phase II trial evaluated ofatumumab in 138 heavily pre-treated relapsed and/or refractory CLL patients, and 
reported ORR of 47-58% with median OS of 13.7-15.4 months.42 Notably, the activity of ofatumumab 
appeared to be independent of prior exposures to rituximab. In 2009, the U.S. FDA granted an accelerated 
approval of ofatumumab for the treatment of CLL patients refractory to both fludarabine and alemtuzumab. 
 

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While various treatment options are available for relapsed/refractory CLL patients, they do not offer durable 
remissions, are certainly not curative, and are frequently toxic. In most cases, the goal of second- or high-
lines of treatment is to bridge patients into the next treatment or to reduce tumor burden before 
hematopoietic stem cell transplant.  
 
2.5.5 
Stem Cell Transplantation:   
Median age of CLL patients at diagnosis is 72.43 Given the advanced age and relatively benign course of 
the disease in many patients, few are considered for aggressive treatments such as hematopoietic cell 
transplantation. Still, stem cell transplant remains as the only curative option for CLL to date, and has 
demonstrated improvement in transplant-related mortality. This option is currently reserved to those small 
subsets of patients with good performance status and high-risk features, such as 17p deletion or 
refractoriness to prior therapies.  
 
2.5.6 
Targeted Tyrosine Kinase Inhibitors  
Orally bioavailable kinase inhibitors are currently being developed.44 Idelalisib (CAL-101, GS-1101) is a 
selective inhibitor of the p110δ isoform of PI3Kδ. Firocari et al. reported a phase 1 study that enrolled 54 
heavily pretreated relapsed/refractory CLL patients, and treated them with continuous once- or twice-daily 
doses ranging from 50 to 350 mg per dose.45 After a median of 9 months drug exposure, ORR was 39%, 
and nodal PR was 50% (defined as 50% reduction of lymph node size from baseline). Median PFS was 17 
months, which increased to 29 months for those receiving 150 mg twice per day or greater. Dose-limiting 
toxicities were not observed, and potentially treatment-related adverse events (fatigue, rash, diarrhea, 
respiratory tract infections, and reversible increases in hepatic transaminases) resulted in discontinuation 
of treatment in only 7% of patients. Because PI3Kδ influences clonal expansion and differentiation of 
suppressor T cells, some of these events, particularly diarrhea and/or colitis, may represent on-target 
toxicities of idelalisib. 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.  
 
Given promising response rates of kinase inhibitors, investigators have started using these kinase inhibitors 
in combinations with chemotherapy, monoclonal antibodies, and other kinase inhibitors. The majority of 
these studies remain early in accrual and maturity. Idelalisib has been studied in combination with rituximab 
versus placebo and rituximab.46  Sharman et al. demonstrated that the median PFS was not reached in 
idelalisib arm as compared to 5.5 months in the placebo arm (hazard ratio for progression or death in the 
idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus placebo had improved rates of ORR 
(81% vs. 13%; odds ratio, 29.92; P<0.001) and OS at 12 months (92% vs. 80%; hazard ratio for death, 0.28; 
P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 
35% of those receiving placebo and rituximab.  
 
Ibrutinib also gained FDA approval in 2014 as a treatment for CLL who had at least one prior therapy or 
who has deletion 17p. Reported clinical experiences as a single-agent and in combinations with ibrutinib 
will be discussed in detail in section 2.6.2. 
 
2.5.7 
Other Options 
The intrinsic apoptotic pathway is often dysregulated in relapsed CLL/SLL due to a deficiency in pro-
apoptotic proteins such as TP53 and overexpression of anti-apoptotic proteins such as Bcl-2. ABT-199 is a 
selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor that can trigger apoptosis. Seymour et 
al looked at 56 patients were enrolled with a median time on study of 10.0 months. ABT-199 showed 
activity in patients with relapsed/refractory CLL with a response rate of 84% including 20% CR and CR 
with incomplete marrow recovery (CRi). The most common adverse events (all grades involving 25% or 
greater patients) were diarrhea (46%), neutropenia (43%), fatigue (34%), upper respiratory tract infection 
(29%), and cough (25%). Grade 3 or 4 adverse events occurring in 4 or more patients were neutropenia 
(41%), TLS (11%), thrombocytopenia (10%), hyperglycemia (10%), anemia (7%), and febrile neutropenia 

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(7%). This study is continuing enrollment using a revised dosing schedule designed to reduce the identified 
risk of tumor lysis syndrome. A phase 2 monotherapy study in patients with relapsed CLL patients with 
deletion 17p has commenced as well as combination studies with either rituximab or obinutuzumab in 
patients with relapsed CLL. 47 
 
2.6 
Ibrutinib 
 
2.6.1 
Mechanism of Action, Distribution, Metabolism and Clearance48 
Ibrutinib (PCI-32765) is a covalent BTK inhibitor, which blocks BCR signaling and induces apoptosis of 
malignant B cells.49 In vitro, ibrutinib forms a potent irreversible bond with cysteine-481 residue at the 
active site of BTK (IC50 = 0.39 nM), and results in sustained inhibition of BTK catalytic activity and 
enhanced selectivity over other kinases that do not contain a cysteine at this position. When added directly 
to human whole blood, ibrutinib inhibits signal transduction from the BCR (IC50 = 80 nM) as assayed by 
anti-IgM stimulation followed by CD69 expression.50 In human B cells, ibrutinib blocked the transcriptional 
up-regulation of B-cell activation genes within 6 hours. 1-hour pulse exposure of ibrutinib followed by 
washout was sufficient to prevent up-regulation of these genes, indicating that ibrutinib acts as an 
irreversible inhibitor of the BCR pathway.51  
 
The plasma protein bindings of ibrutinib and PCI-45227 are 97.3% and 91.0%, respectively. The apparent 
steady-state volume of distribution (Vdss/F) is approximately 10,000L (based on non-compartmental and 
population PK analyses), suggesting extensive distribution to peripheral tissues and/or binding to 
macromolecules in circulation. The blood-to-plasma ratio around Tmax is approximately 0.7. 
 
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 9 hours, with a median time to maximum plasma 
concentration (Tmax) of 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. Less than 1% 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. 
 
Excretion is predominantly via feces (approximately 80% recovered within 2 days), and less via urine 
(~8%). The apparent clearance in subjects with B-cell malignancies is high: in the order of 1000 L/h. The 
half-life of ibrutinib is 4-6 hours. Overall, these pharmacokinetic (PK) characteristics resulted in minimal 
accumulation of both parent compounds and metabolite PCI-45227 on repeated daily dosing of ibrutinib. 
Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose exposure. 
 
2.6.2 
Clinical Experience in CLL  
Once-daily administration of ibrutinib causes sustained inactivation of BTK resulting inhibition of BCR 
signaling and tumor microenvironment interactions.52,53_ENREF_53 The phase 1b/2 multicenter ibrutinib 
trial reported by Byrd et al. involved 85 relapsed CLL patients where 51 received 420 mg, and 34 received 
840 mg.54,55 ORRs were 71% in both dosing groups, with an additional 15-20% had a partial response with 
lymphocytosis (PR-L). At 26 months, the estimated PFS was 75%, and OS was 83%. A single-agent 

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ibrutinib was overall well tolerated, while commonly observed side effects included thrombocytopenia, 
diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, 
rash, fever, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis and dizziness. When 
ibrutinib was compared to ofatumumab in 391 previously treated CLL in a randomized phase 3 study, 
ibrutinib achieved significantly higher ORR (42.6% vs. 4.1%, p<.001) and showed survival benefit (12-
month OS: 90% vs. 91%, hazard ratio 0.43, p=.005).55    
 
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 a well-tolerated initial therapy, and led to ORR of 71% 
(13% had CR; 3% had nodal PR, 55% ad PR).56 In the high-risk CLL population with TP53 mutation, a 
ibrutinib was an active single-agent treatment as an initial therapy as well as for relapsed or refractory CLL, 
and led to ORR of 97% (55% had PR; 42% had PR-L).57  
 
In July 2014, ibrutinib received a full approval in the US for CLL patients who have received at least one 
prior therapy, and for the patients with 17p deletion. Response to ibrutinib appears to be independent of 
clinical and genomic risk factors, and it currently stands as the sole FDA-approved agent with the treatment 
indication for CLL with 17p deletion.  Long-term data regarding responses and toxicity are still maturing 
for ibrutinib. Notably, a 3-year post-initiation data of 132 previously untreated and relapsed/refractory CLL 
patients on ibrutinib did not show new safety signal.58 The observed median duration of response was not 
reached for all treated patients on study, while it was 25 months for the subset with deletion 17p. 30-month 
PFS was 96% among patients who received ibrutinib as a frontline.59 
 
Ibrutinib has been investigated in combinations with other agents including chemoimmunotherapies in 
CLL, and early experiences were reported to date. Barrientos et al. reported on 30 patients with 
relapsed/refractory CLL/SLL that received up to 6 cycles of BR with a continuous fixed ibrutinib dose of 
420 mg/day.60 With the median treatment duration of 16 months, the ORR was 93% (28/30 patients, 
including 5 CRs and 3 nodal PRs), and one additional patient achieved a PR-L. The estimated 12 month 
PFS was 90%, and the responses appeared to be independent of high-risk features. The most frequently 
reported adverse events were diarrhea (70%), nausea (66.7%), fatigue (46.7%), neutropenia (40%) and 
upper respiratory tract infection (36.7%). Adverse events in grade 3 or higher in severity included 
neutropenia (40%), maculopapular rash and fatigue (10% each), and thrombocytopenia, febrile neutropenia, 
and cellulitis (6.7% each).  
 
Ibrutinib in combination with rituximab was investigated in two different phase II trials. The first study 
reported 40 high-risk CLL patients who were treated with daily ibrutinib and 6 cycles of rituximab.61 At 
the median follow up of 14 months, 32 of 40 patients continue on therapy without disease progression. 
Based on 2008 IWCLL guideline, ORR was 95% (87% in PR; 8% in CR), and one patient in CR achieved 
minimal residual disease negativity by flow cytometry. Notably, the response rate of patients with 17p 
deletion or TP53 mutation was 90%, with the majority of them achieving PR. Treatment generally was well 
tolerated, with infectious complications being the most common adverse event. 8 patients came off study; 
3 patients died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), 1 died 
from unrelated respiratory and cardiovascular failure, 2 came off study due to possible ibrutinib-related 
toxicity (one subdural hematoma, one grade 3 mucositis), 1 had progressive disease, and 1 proceeded to 
stem cell transplantation. The second study randomly assigned 93 relapsed CLL patients to either ibrutinib 
alone or ibrutinib and rituximab, and reported more rapid abrogation of lymphocytosis in the combination 
arm.62 
 
Byrd et al. reported on ibrutinib in combination with ofatumumab for treatment of relapsed CLL/SLL.  For 
the 27 enrolled CLL/SLL patients, ORR defined by IWCLL criteria was 100%, PFS was 100% at the 
median follow-up of 9.8 months.63 89% of CLL/SLL/prolymphocytic leukemia (PLL) patients remain on 
study and only one patient has discontinued treatment by proceeding to stem cell transplant. The majority 
of adverse events were grades 1 or 2, and no grade 3 or 4 infusion reactions, neutropenia, or 
thrombocytopenia have been observed. 

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Limitations of ibrutinib have been identified as clinical experiences are accumulating. First, deep responses 
with a single-agent ibrutinib are rare. When ibrutinib was combined with other agents, CR rate increased 
to 8% (ibrutinib/rituximab)61 and 16% (ibrutinib plus BR),64 which still fall short of conventional 
approaches.34,35 Second, acquired mutations in BTK and in phospholipase C-gamma 2 (PLCγ2), a direct 
downstream target of BTK, were identified in six CLL patients who developed secondary resistance to 
ibrutinib.65,66 Among them, five showed a cysteine-to-serine mutation in BTK (C481S), which disrupts the 
covalent binding between the drug and the kinase, and thereby dramatically decreases the potency of 
ibrutinib. Two patients, including one with C481S mutation, had gain-of-function mutations in PLCγ2 
leading to autonomous BCR signaling.65 
 
2.7 
Summary of Clinical Safety  
 
A brief summary of safety data from monotherapy and combination therapy studies is provided in below. For 
more comprehensive safety information please refer to the current version of the IB. Additional safety 
information may be available for approved indications in regional prescribing labels where the study is 
conducted. 
 
For monotherapy studies: 
Pooled safety data for a total of 1318 subjects treated with ibrutinib monotherapy in 13 studies that have 
completed primary analysis or final analysis as of the 31 May 2016 cutoff date for the current IB update in B-
cell malignancies are summarized below.  
 
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving ibrutinib as 
monotherapy (N=1318): 
 
Most frequently reported TEAEs  
 15% a   
Most frequently reported Grade 3 
or 4 TEAEs  3% b 
Most frequently reported Serious 
TEAEs  2% c 
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Pyrexia 
Hypertension 
Diarrhea   
 
Neutropenia 
Atrial fibrillation 
 
Upper respiratory tract infection  
Thrombocytopenia 
Edema peripheral    
 
 
a Source is Table 6 of IB (v11), b Source is Table 8 of IB (v11), c Source is Table 9 of IB (v11). 
 
Rarely, in less than 1% of cases, pneumonia was attributed to the infection of Pneumocystis jirovecii. Most 
cases of Pneumocystis pneumonia (PCP) were reported as a single case from different monotherapy and 
combination studies. 
 
For combination therapy studies:  
Pooled safety data for a total of 423 subjects treated with various therapies in combination with ibrutinib from 
4 studies conducted in B-cell malignancies, which included 1 randomized-control study, are summarized 
below. Therapies used in combination with ibrutinib in these studies, included BR (bendamustine and 
rituximab), FCR (fludarabine, cyclophosphamide, and rituximab), ofatumumab, and R-CHOP (rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone).  
 
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423): 

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Most frequently reported TEAEs  
 20% a   
Most frequently reported Grade 3 
or 4 TEAEs  3% b 
Most frequently reported Serious 
TEAEs  2% c 
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Anemia 
Pyrexia 
Hypertension 
Neutrophil count decreased 
Anemia 
Fatigue 
Diarrhea 
  
Cellulitis 
a Source is Table 10 of IB (v11), b Source is Table 12 of IB (v11), c Source is Table 13 of IB (v11). 
 
Rarely, in less than 1% of cases, pneumonia was attributed to the infection of Pneumocystis jirovecii. Most 
cases of Pneumocystis pneumonia (PCP) were reported as a single case from different monotherapy and 
combination studies. 
 
2.7.1 
Clinical and scientific justification for protocol design 
Combinations of chemoimmunotherapies as front-line CLL treatment have significantly improved patient 
outcomes. Nevertheless, approximately 10% of CLL patients do not respond to fludarabine-based therapies 
and approximately half eventually progresses with relapsed or refractory diseases. Chemoimmunotherapies 
also leads to short- and long-term toxicities. These limitations call for a novel treatment approach that is 
both efficacious and safe. 
 
BCR signaling, a pathway critical for malignant B-cell activation, is pharmacologically targetable.  
Inhibition of BTK with ibrutinib was proven to be effective and well tolerated in CLL,52 leading to FDA-
approval of ibrutinib for CLL patients who had at least one prior treatment or CLL with deletion 17p.  The 
use of ibrutinib upfront is justified in patients with deletion 17p, and the proposed combination of ibrutinib 
and fludarabine may be particularly desirable in this patient population. 
 
Along with the accumulation of clinical experiences, a single-agent ibrutinib is identified to have several 
limitations. First, deep responses are infrequent.  CR was seen in only 2% of relapsed or refractory CLL54 
and in 13% of treatment-naïve CLL.56 When ibrutinib was combined with other agents, CR rate increased 
to 8% (ibrutinib/rituximab)67 and 16% (ibrutinib/bendamustine/rituximab),64 which still fall short of 
conventional approaches.34,35  Moreover, acquired mutations in BTK and phospholipase C-gamma 2 
(PLCγ2), a direct downstream target of BTK, were identified in 6 CLL patients who developed secondary 
resistance to ibrutinib.65,66 Among them, five showed a cysteine-to-serine mutation in BTK (C481S), which 
disrupts the covalent binding between the drug and the kinase, thereby dramatically decreasing the potency 
of ibrutinib.65 We hypothesize that the addition of a second agent could augment the depth of response and 
prevent drug resistance. This constitutes one rationale for the trial design.  
 
Notably, T-cells in CLL are capable of stimulating tumor cells and promoting resistance to apoptosis 
through CD40 ligand and other pathways.9,10 In vivo, T-cells and CLL cells were shown to aggregate and 
form ‘proliferation centers’ within bone marrow and lymphoid tissues, and these rallied cells were 
necessary for CLL cell proliferation.68 Using fludarabine as the second agent provides a mean to target 
these T-cells. 
 
In this context, immunotherapy is an attractive option for long-term disease control. Allogeneic stem cell 
transplantation set the paradigm of a curative approach using immune reconstitution; however, it is only 
available for a minority of patients. The clinical successes with chimeric antigen-receptor (CAR) T cells 
provide a strategy for more general application of T-cell immunotherapy in CLL. However, T-cells in CLL 

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are functionally69 and phenotypically11 defective, or  “pseudo-exhausted”, due to inhibitory signals from 
leukemic B cells - such as CD200, PD-L1 and B7-H38 - and these signals appear to reduce the efficacy of 
CAR T cells. Fludarabine has been used successfully as a preparative agent before immunotherapies and 
can promote reconstitution of the T-cell compartment through homeostatic proliferation.70 
 
Thus, we view CLL as a clonal proliferation of auto-reactive B-cells that escape immune surveillance, and 
are stimulated through BCR signaling and T-cell interaction.  We propose to combine ibrutinib with a short-
course fludarabine to achieve two goals: first, eliminate or greatly decrease T-cell help towards CLL cells; 
and second, replace the dysfunctional T-cell population.  Fludarabine, a purine analog cytotoxic to both B 
and T cells,32,72,73 is a biologically plausible addition to ibrutinib with a large body of experience in CLL 
treatment.32,34,71   In addition, fludarabine is frequently used as a part of conditioning regimen during 
hematopoietic stem cell transplant72,73 and adoptive cell transfer74,75 with an aim to deplete lymphocytes 
and reconstitute immune microenvironment. Preclinical and clinical evidences support the immune 
modulatory role of fludarabine and subsequent recovery of T cells in CLL. Notably, reconstitution of CD4+ 
T, CD8+ T, and NK cells were demonstrated in CLL after treatment with fludarabine.70 Regulatory T cells 
decreased after fludarabine exposure.76  
 
We hypothesize that recovering T-cell populations after a short-course fludarabine will have an improved 
functional capacity, and can exert anti-leukemic effects by the recovery of immune surveillance function.  
We consider the combination of ibrutinib and fludarabine as a possible platform to which immune 
therapeutic approaches, such as vaccines, CAR T-cells, or checkpoint inhibitors, may be added in 
subsequent steps.  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. We will compare the correlative data to our 
experience with single-agent ibrutinib in over 70 patients, and the ongoing study using fludarabine, 
cyclophosphamide, and ofatumumab in previously untreated CLL patients. 
 
The following specific issues have been considered in the study design: 
• 
Studying untreated CLL/SLL is justifiable as the side effect profile of ibrutinib is favorable and 
fludarabine is the current standard front-line agent.  
• 
The combination of ibrutinib and chemotherapy has been well tolerated64 and there are ongoing 
clinical trials combining ibrutinib with chemoimmunotherapies, including a phase III study of BR 
plus ibrutinib (NCT01611090), a phase II study of FCR plus ibrutinib (NCT02251548), and a phase 
III study with an arm for ibrutinib plus rituximab (NCT02048813). 
 
3.0 
STUDY DESIGN  
This is a phase II single center trial. It is a prospective, single-arm, open-label study of ibrutinib and a short-
course fludarabine in previously untreated subjects with CLL or SLL.  Each cycle is 28 days.  Patients will 
initiate ibrutinib first for cycle 1 and 2, followed by the addition of short-course fludarabine for cycle 3 and 4. 
Ibrutinib will be given continuously until disease progression or intolerable side effects.  
 
 

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4.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
 
4.1 
Inclusion Criteria 
 
1. Men and women with histologically confirmed disease as defined by the following: 
• 
CLL: clonal B-lymphocytosis ≥ 5,000 cells/L . 
• 
SLL: lymphadenopathy with the tissue morphology of CLL but that are not leukemic, < 5,000 cells/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. Treatment naïve CLL/SLL patients  
• 
Treatment-naïve CLL indicates no prior anti-CLL therapy. Anti-CLL therapy includes chemotherapies, 
monoclonal antibodies, and targeted agents with known or reasonably expected anti-leukemic activity. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
5. ANC > 750/uL, platelets > 50,000/uL 
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 method of birth control (e.g., 
implants, injectables, combined oral contraceptives, some intrauterine devices, complete abstinence, or 
sterilized partner) and a barrier method (e.g. condoms, vaginal ring, sponge, etc.) during the period of 
therapy and for 90 days after the last dose of study drug 
• 
Complete abstinence is a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and 
usual lifestyle of the subject. 
7. Willing and able to participate in all required evaluations and procedures in this study protocol including 
swallowing capsules without difficulty 
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) 
 
4.2 
Exclusion Criteria 
 
• 
Transformed CLL, including Hodgkin and non-Hodgkin lymphoma 
• 
Active autoimmune hemolytic anemia or thrombocytopenia  

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• 
Known bleeding disorders 
• 
Impaired hepatic function: Total bilirubin ≥1.5 x upper limit of normal unless due to Gilbert's disease, 
AST/ ALT ≥ 2.5 x institutional upper limit of normal unless due to infiltration of liver, Child-Pugh class 
B or C 
• 
Impaired renal function: estimated GFR < 30ml/min/1.73m2 based on CKD-EPI 
• 
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 
• 
Concomitant immunomodulatory therapy, chemotherapy, radiotherapy or experimental therapy 
• 
Active Hepatitis B or Hepatitis C infection   
• 
HIV infection 
• 
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. 
• 
Individuals < 18 years old  
• 
Known hypersensitivity to any component of ibrutinib or fludarabine 
• 
Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K antagonists. 
• 
Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical 
cancer, or other cancer from which the subject has been disease-free for ≥ 2 years or which will not limit 
survival to < 2 years. 
• 
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 
• 
Major surgery within 4 weeks of first dose of study drug. 
• 
Currently active, clinically significant cardiovascular disease such as 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, or unstable angina, or acute coronary syndrome within 
6 months of screening. 
• 
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. 
 
5.0 
TREATMENT PLAN  
 
5.1 
Drug administration 
Ibrutinib is an orally administered product. Study drug ibrutinib administration will take place in the outpatient 
facility of the NIH clinical center or at the patient’s home. The drug dose is 420 mg PO daily. There is one 
specific dietary restriction to avoid grapefruit juice and Seville oranges due to CYP450 3A4 inhibition. Each 
dose of ibrutinib is to be taken with 8 ounces (approximately 240mL) of water. The capsule should be 
swallowed intact and subjects should not attempt to open the capsule or dissolve them in water. Ibrutinib will 
be given daily until disease progression or intolerable side effects.  
 
Fludarabine is given as an intravenous infusion on cycle 3 and 4. 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.  Per PI discretion, a central 
line may be placed in select patients. Fludarabine dose is 25 mg/m2/day on days 1-5 of cycles 3 and 4. 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; 

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• 
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. 
 
5.2 
Therapy schedule:  All cycles will be 28 (+/- 5) days long. 
• 
Cycle 1 and 2: ibrutinib 420mg PO daily on day 1-28 
• 
Cycle 3 and 4: ibrutinib 420mg PO daily on day 1-28, fludarabine 25mg/m2/day on day 1-5 
• 
Cycle 5 and subsequent cycles up to C27: ibrutinib 420mg PO daily on day 1-28 
 
5.3 
Prophylactic Medications:   
• 
Allopurinol 300mg PO once daily (or alternative agent in case the subject cannot tolerate 
allopurinol) during cycle 3 and 4 on days 1-7 for all subjects 
• 
Sulfamethoxazole/trimethoprim DS PO once daily 3 times per week (or alternative agent in case 
of sulfa allergy) from cycle 1 to 9 and beyond at the discretion of the PI 
• 
Acyclovir 800 mg PO twice daily or valacyclovir 500mg PO once daily at the discretion of the PI 
(not mandatory) 
 
5.4 
Holding and dose adjustments of study drug administration in the case of treatment related 
toxicity 
 
5.4.1 Cytopenia:  
Drug 
Cycle 
Condition at the 
start of cycle 
Action* 
Ibrutinib 
1 and 
onwards 
ANC <500/μL 
OR 
PLT <50,000/μL 
 
Check CBC with differential weekly.  
Hold ibrutinib if cytopenia persists for ≥ 7 days OR if PLT<50,000/μL 
with bleeding. 
Resume ibrutinib when ANC ≥750/μL AND PLT ≥50,000/μL. 
• 
First occurrence: Resume ibrutinib at 420 mg once daily (original 
dose). 
• 
Second occurrence: Resume ibrutinib at 280 mg once daily. If 
cytopenia does not recur after 2 cycles of ibrutinib 280 mg once 
daily, investigator may increase ibrutinib to 420 mg once daily. 
Fludarabine 
3 and 4 
HGB <11 g/dL 
with indications of 
autoimmune 
hemolysis 
Omit fludarabine. 
 
 
ANC 750 - 
<1,000/μL  
OR  
PLT 50,000 - 
<75,000/μL 
Defer fludarabine and check CBC with differential weekly. 
Resume fludarabine at original dose when ANC ≥1,000/μL AND PLT 
≥75,000/μL. 
If count recovery does not occur in 8 weeks, omit fludarabine. 
 
 
ANC <500/μL,  
OR 
PLT <50,000/μL   
Defer fludarabine, and check CBC with differential weekly.  
Resume fludarabine at 20% reduced dose when ANC ≥1,000/μL AND 
PLT ≥75,000/μL. 
If count recovery does not occur in 8 weeks, omit fludarabine. 
ANC - absolute neutrophil count; PLT – platelet 
* Dose delay or reduction is not required if cytopenia is considered related to CLL.  

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5.4.2  Atrial fibrillation:   
• 
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 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. 
 
5.4.3 
Non-hematologic toxicities: 
• 
After a grade 3 or higher non-hematological toxicity (despite optimal supportive care) resolves, 
ibrutinib will be restarted as follows;  
 
Occurrence 
Action 
 1st  
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at the original 
dose level (420mg daily). 
2nd  
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at one dose level 
lower (280mg daily). 
3rd  
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at one dose level 
lower (140mg daily). 
4th 
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 withheld for a toxicity of 28 consecutive days the study drug should 
be discontinued. However, if clinical benefit outweighs the risk of restarting treatment then patient 
may restart study drug after > 28 consecutive days off study drug per PI discretion. 
• 
For fludarabine, after a grade 3 non-hematological toxicity (despite optimal supportive care), when 
the toxicity resolves to grade 2 or lower and clinical benefit outweighs the risk, treatment can be 
restarted with 20% dose reduction on the subsequent cycle. Patients experiencing ≤ Grade 2 side 
effects may continue treatment. Supportive measures as appropriate should be taken to minimize 
side effects. An interruption of study drug administration is permissible. In select cases where a 
subject has uncomfortable grade 2 toxicities, dose may be reduced by one dose level per PI 
discretion. 
 
Dose changes must be recorded in the Dose Administration eCRF. 
 
5.4.4 
Dose modification for hepatic impaired subjects: 
• 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant hepatic 
impairment at the time of screening (Child- Pugh class B or C) are excluded from study 
participation.  
• 
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).  

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• 
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 5.4.3.  
 
5.5 
Holding of Study Drug Administration 
 
5.5.1 
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. 
 
5.5.2 
Medically Necessary Conditions to Hold Study Drugs: 
• 
If medically necessary reasons to hold ibrutinib occur during treatment (i.e. concurrent infection, 
impending workups for diagnostic and/or therapeutic purposes), ibrutinib can be held based on 
the study team’s discretion. 
• 
If medically necessary reasons to hold fludarabine occur during treatment (i.e. concurrent 
infection, emergence of autoimmune cytopenia, impending workups for diagnostic and/or 
therapeutic purposes), fludarabine can be delayed up to 2 cycles while continuing ibrutinib until 
the medical reasons to hold fludarabine resolve or return to baseline. If fludarabine is delayed 
beyond 2 cycles, fludarabine will be omitted and the patient will continue treatment with ibrutinib 
only. 
• 
Supportive medications including allopurinol, and acyclovir (if indicated) intended to start at 
cycle 3 will be delayed until fludarabine starts or not given if fludarabine is omitted. Weekly labs 
intended for cycles 3 and 4 will be delayed until fludarabine starts or not performed if fludarabine 
is omitted. 
 
5.5.3 
Permanent discontinuation of study drug administration in case of treatment related 
adverse events:   
• 
Serious or life threatening cardiac arrhythmias (grade 3 or 4)  
• 
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 7.3 
• 
Pregnancy or unwillingness to use acceptable method of contraception 
 
Patients who will not be able to receive further study drug administration will be followed for safety 
and after resolution of the event will continue to be followed at regular intervals and will undergo 
reassessment of disease as outlined in section 6 and 7. 
 
5.6 
Supportive Care (non-investigational) 
 
5.6.1 
Blood Products:  Patients will be transfused packed red blood cells and platelets as clinically 
indicated.  All required blood products will be irradiated prior to transfusion.   
5.6.2 
Growth Factors:  Filgrastim or peg-filgrastim may be used to accelerate count if ANC < 500/uL 
at the PI’s discretion, for example, for febrile neutropenia.  
5.6.3 
Anti-infective agents will be used as indicated for treatment of intercurrent infections. 
5.6.4 
PCP prophylaxis: Sulfamethoxazole/trimethoprim DS PO once daily 3 times per week (or 
alternative agent in case of sulfa allergy) from cycle 1 to 9 and beyond, at the discretion of the PI. 
Patients who may be at an increased risk of PCP infection include those who are taking long-term 

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high-dose steroids or immune suppressants, and those who had prior PCP infection. Patients 
allergic to sulfa drugs who are deemed appropriate for prophylaxis may be given an alternative 
agent at the discretion of the PI.  
5.6.5 
Anti-viral prophylaxis: Acyclovir 800 mg PO twice daily or valacyclovir 500mg PO once daily 
may be used the discretion of the PI (not obligatory).   
 
5.7 
Permitted and Non Permitted Concomitant Medications (Investigators Brochure) 
 
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 only during cycles with ibrutinib alone, but not during cycle 
3 and 4 when fludarabine is added. Treatment for autoimmune cytopenias should not exceed 14 days at doses 
that do not exceed 100mg per day of prednisone or equivalent.  
 
5.7.1   Guideline for Use of CYP Inhibiting Drugs 
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong CYP3A or moderate 
CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  
  
• 
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, posaconazole, or cobicistat) must be used, 
reduce ibrutinib dose to 140 mg or withhold treatment temporarily (for 7 days or less). Subjects should 
be monitored for signs of ibrutinib toxicity.  
• 
If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, 
ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, 
verapamil, amiodarone, or dronedarone) must be used, reduce ibrutinib to 140 mg (for 840 mg/day 
dose, reduce to 280 mg) for the duration of the inhibitor use. Avoid grapefruit and Seville oranges 
during ibrutinib treatment, as these contain moderate inhibitors of CYP3A. 
• 
No dose adjustment is required in combination with mild inhibitors. 
• 
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and St. 
John’s Wort). Consider alternative agents with less CYP3A induction. 
• 
A list of common CYP3A inhibitors and inducers is provided in Appendix 3 of the IB.  A 
comprehensive 
list 
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. 
• 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please refer 
to the current version of the IB. 
 
5.7.2  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.  
 
5.7.3  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. 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. For 
guidance on ibrutinib and the use of anticoagulants during procedures/surgeries see Section 5.5. 
 

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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.   
 
5.8 
Special instructions for patients 
 
5.8.1 
Immunizations:  Live vaccines are contraindicated in this patient population. Subjects who would 
like to receive other routine non-attenuated vaccinations will be allowed to do so. Patients will be 
advised not to receive live viral vaccines. The ability to generate an immune response to any 
vaccine following administration of ibrutinib has not been studied. 
 
5.8.2 
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 that 
periodic abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation methods or 
withdrawal, are not acceptable methods of contraception. 
 
5.9 
Prohibited Concomitant Medications 
• 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy are prohibited while 
the subject is receiving ibrutinib treatment.   
• 
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. 
• 
Corticosteroids for the treatment of the underlying disease is prohibited.  Corticosteroids for the treatment 
of non-cancer related reasons for longer than 14 consecutive days at doses >20mg/day of prednisone or 
equivalent, or at doses >100mg of prednisone or its equivalent at any time point is prohibited.   
 
 
6.0 
CLINICAL MONITORING  
 
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.  
 
Results from other NIH protocols may be used as a part of the study evaluation. Selected results performed 
from 
outside 
institutions 
are 
accepted, 
which 
are 
viral 
studies, 
flow 
cytometry, 
CT 
of 
neck/chest/abdomen/pelvis, and FISH. 
 
6.1 
Study Evaluations: Screening and Baseline (see schedule of events Appendix A) 
 
Screening:  
Screening evaluation will include the following (also see schedule of events).  
• 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 evaluation 
• Physical exam will be performed, and subjects will be monitored clinically for atrial fibrillation 
• Concomitant medication review 

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• Complete blood count (CBC) with differential  
• Acute Care Panel (includes Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen) 
• Mineral Panel (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 
• Coagulation panel (includes PT, PTT) 
• Beta-2 microglobulin (B2M) 
• Haptoglobin 
• Direct antiglobulin test (DAT) 
• Iron Studies (includes ferritin, transferrin, iron) 
• Folate, Vitamin B12 
• Viral serologies for hepatitis B and C, HIV 1/2. For individuals with a positive hepatitis B core 
antibody, HBV DNA PCR will be performed to screen for subclinical infection within 12 months 
preceding the start of study drug.  
• For females of childbearing potential, one negative pregnancy tests sensitive to 50 mIU within 2 weeks 
prior to starting study drug 
• Flow cytometry panel for CLL (may be done on blood and/or bone marrow and/or lymph node) or 
immunohistochemistry of lymph node or bone marrow 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.  
• EKG within 3 months prior to starting study drug 
 
Baseline (day -28 to day 0):  
Baseline evaluation will include the following (also see schedule of events).  
• 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 evaluation 
• Physical exam will be performed, and subjects will be monitored clinically for atrial fibrillation 
• Concomitant medication review 
• HLA typing (if clinically indicated) 
• CBC with differential 
• Acute Care Panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen) 
• Mineral Panel (Phosphorus, Magnesium, Albumin, and Calcium) 
• Total Protein, CK, Uric Acid, and LDH  
• Hepatic Panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin) 
• Reticulocyte count 
• Coagulation panel (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) 
• For females of childbearing potential, pregnancy test 
• Lymphocyte phenotyping (T, B, NK)  
• IGHV mutation analysis (as this test does not change with time, any prior report is acceptable) 

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• Flow cytometry panel (optional)  
• Bone marrow aspirate and biopsy within 3 months of starting treatment 
• Peripheral blood 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).  
• Lymph node biopsy for research if the patient is willing and has an accessible lymph node (optional) 
• Lymphapheresis for research (optional) 
• Research blood (up to 80ml) 
 
6.2 
On therapy evaluations (see schedule of events Appendix A) 
 
From cycle 1 to 6 (+/- 5-day window): 
Prior to each cycle, the following assessments will be completed. If the assessments have been already 
performed within 5 days of the study drug initiation as a part of screening or baseline evaluations, the study 
team can decide whether these assessments may or may not be repeated. 
• 
Interval History 
• 
ECOG performance status evaluation  
• 
Physical exam 
• 
Concomitant medication review  
• 
CBC with differential 
• 
Acute Care Panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen) 
• 
Mineral Panel (Phosphorus, Magnesium, Albumin, and Calcium) 
• 
Total Protein, Uric Acid, and LDH 
• 
Hepatic Panel (Alk Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin) 
• 
Reticulocyte count 
• 
Beta-2 microglobulin (B2M) 
• 
Direct antiglobulin test (DAT) 
• 
For females of childbearing potential, repeat pregnancy test 
• 
Research blood (up to 80ml) 
 
Additional blood draws, procedures, or imaging include (+/- 5-day window, except for CT scan and 
bone marrow biopsy):  
 
Cycle 3&4 
• 
Prior to Cycle 3 (within day -14 to 0): Lymphocyte phenotyping (T, B, NK), CT of neck/chest/ 
abdomen/pelvis 
• 
Cycle 3&4 Day 5 (+/- 5 days): Research blood (up to 80ml, optional) 
• 
Cycle 3&4 Day 14, and 22 (+/- 5 days): CBC with differential (may be performed outside of NIH), 
research blood (up to 80ml) (if the blood was drawn at the NIH) 
 
Cycle 5 
• 
Cycle 5 Day 1 (+/-5-day window): Lymphocyte phenotyping (T, B, NK) 
 
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). 
 
After cycle 6 (+/- 14-day window): 
Following assessments will be done every 3 months while on therapy until disease progression or 
intolerable side effects. 
• 
Interval History 
• 
ECOG performance status evaluation  

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• 
Physical exam 
• 
Concomitant medication review  
• 
CBC with differential 
• 
Acute Care Panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen) 
• 
Mineral Panel (Phosphorus, Magnesium, Albumin, and Calcium) 
• 
Total Protein, Uric Acid, and LDH 
• 
Hepatic Panel (Alk Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin) 
• 
Reticulocyte count 
• 
Beta-2 microglobulin (B2M) 
• 
Direct antiglobulin test (DAT) 
• 
For females of childbearing potential, repeat pregnancy test 
• 
Research blood (up to 80ml) 
 
6.3 
Response assessment (see schedule of events Appendix A) (+/- 30-day window) 
Response assessment will be performed after 6 cycles, and annually (at the anniversary date of the first dose of 
study drug).  
 
• 
Interval History 
• 
ECOG performance status evaluation  
• 
Physical exam 
• 
Concomitant medication review  
• 
CBC with differential 
• 
Acute Care Panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen) 
• 
Mineral Panel (Phosphorus, Magnesium, Albumin, and Calcium) 
• 
Total Protein, Uric Acid, and LDH 
• 
Hepatic Panel (Alk Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin) 
• 
Reticulocyte count 
• 
Coagulation panel (PT, PTT) 
• 
Serum free light chains, quantitative immunoglobulins  
• 
Beta-2 microglobulin (B2M) 
• 
Haptoglobin 
• 
Direct antiglobulin test (DAT) 
• 
For females of childbearing potential, pregnancy test 
• 
Lymphocyte phenotyping (T, B, NK)  
• 
Flow cytometry panel (optional)  
• 
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.  
• 
Bone marrow biopsy after 6 cycles (mandatory). May also obtain annually starting at the anniversary 
date of the first dose of the study drug (optional). After 1 year on study, bone marrow biopsy and 
aspirate may be performed 3 months ± 15-days after the patient met CT criteria and hematologic criteria 
for complete response (optional). 
• 
EKG if medically indicated 
• 
Lymphapheresis for research (optional) 
• 
Lymph node biopsy for research if the patient is willing and has an accessible lymph node. Up to 3 
lymph node biopsies may be obtained for research at any time during therapy (optional, with at least 4 
weeks between biopsies).  
• 
Research blood (up to 80ml) 
 

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6.4 
At progression evaluation (see schedule of events Appendix A)  
All response assessments as listed in 6.3 may be performed at progression. Additional optional studies may be 
performed which includes the following: 
• Serum protein electrophoresis with immunofixation (SPEP) 
• C-reactive protein (CRP) 
• PET/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  
• Peripheral blood interphase FISH with FISH panel containing probes for ATM (11q22.3), D12Z3 (12 
cen), D13S319 (13q14.3), LAMP1 (13q34) and TP53 (17p13.1) 
• IGHV mutational analysis 
 
 
7.0 
CRITERIA FOR RESPONSE 
 
Responses for spleen and lymphadenopathy will be assessed using CT scan scans. In the absence of a CT scan 
assessment by physical exam may be substituted. Response assessments will be made by IWCLL 2018 
guidelines.77 Response includes complete response, partial response, and partial response with lymphocytosis 
(Table 4).  
 
Table 4. 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 lymphocytesC 
< 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 
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. 

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C Patients 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. 
D Complete 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. 
 
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. 
 
 
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 F/U visits 
(not to exceed 550 mL in any 8-week period). 
 
Lymphapheresis: A 4-5 liter lymphapheresis procedure for research may be obtained prior to initiating therapy 
in consenting subjects.  

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BM biopsies and aspirate: A bone marrow biopsy cylinder and up to 10cc of bone marrow aspirate may be 
obtained for research at the time of bone marrow biopsy as indicated in sections 6.1 and 6.2.  
 
Lymph node biopsies: An excisional or core lymph node biopsies may be obtained pre-treatment and after 
treatment. 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. These 
samples will be stored with the subject’s permission for other exploratory laboratory research studies reviewed 
and approved by the IRB and listed in Appendix B.  Research samples will be coded and stored in the secure 
laboratory of Dr. Wiestner.  
 
8.2 
Intended use 
 
These samples will be used for the following intentions. 
1. 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 such PD-L1, PD-1, and CTLA-4 
• 
Genomic profiling of the B- and T-cell repertoire by CDR3 analysis 
• 
Measure pertinent cytokine and chemokine levels 
 
2. To explore mechanisms of clinical response, we will; 
• 
Assess shifts in clonal composition on treatment assessed using interphase FISH and gene sequencing 
for somatic mutations 
 
These specimens will not be used for diagnostic purposes.  
 
Leftover and additional samples will be used for the following descriptive or exploratory ancillary research 
studies which may be done and if done, may be correlated with the presence or absence of response.  Samples 
may also be sent to Pharmacyclics, an AbbVie Company, once an MTA has been established 
 
8.3 
Storage, tracking and disposition of samples and data 
 
Storage: All samples will be stored in the laboratory of Dr. Wiestner.  Samples collected will be de-identified 
prior to storage in the laboratory of the principal investigator following current NHLBI DIR BSI Policy. Efforts 
to ensure protection of patient information include: 
 
• 
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 personal identifier information. 
• 
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.   
 
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.  
 

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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: 
Primary efficacy endpoint is the rate of complete response at 24 weeks or after 6 cycles.  Response to 
treatment will be determined according to IWCLL 2008 criteria incorporating 2012 and 2013 
clarifications pertaining to patients treated with kinase inhibitors.  
 
Primary safety endpoint is the rate of treatment discontinuation within the first 24 weeks or 6 cycles 
due to intolerable side effects. 
 
9.2 
Secondary endpoints: 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
Best response during treatment 
• 
Duration of response 
• 
Minimal residual disease (MRD) state defined by flow cytometry 
• 
Clonal dynamics on treatment assessed using interphase FISH and gene sequencing for somatic 
mutations 
• 
Shifts in cellular and humoral immunity on treatment (e.g. immunoglobulin levels, myeloid-derived 
stromal cells, B-cell repertoire, T-cell subsets including regulatory T cells, T helper 1, T helper 2, T 
helper 17) 
• 
Expression of checkpoint inhibitory molecules such as PD-L1, PD-1, and CTLA-4 
 
9.3 
Sample size  
 
The study will enroll 27 evaluable subjects for response assessment for primary efficacy and safety endpoints.  
Up to 5 additional subjects may be enrolled to account for early discontinuation before completing 6 cycles due 
to non-treatment related reasons. Those subjects with non-treatment related early discontinuation will not be 
evaluable for the primary efficacy and safety endpoints.  
 
As for the primary efficacy endpoint, CR with ibrutinib alone has been reported to be 13% in previously 
untreated CLL population,56 and 0-2% in relapsed/refractory CLL.54,55 When ibrutinib and rituximab were 
combined in high-risk CLL patients, CR rate was 8%.61 Based on the reported data, a CR rate exceeding 20% 
would generate an interest for further studies.  We will use a Simon’s minimax two-stage design to test the null 
hypothesis (H0) that the CR rate in the study is ≤5% against the alternative hypothesis (H1) that it is >5% with 
type I error of 0.05.  If the true CR rate is 20%, the study using the following two-stage design has 80% power. 
In the first stage, we will enroll 13 subjects and assess CR rate after 6 cycles.  If there is no CR in these 13 
subjects, we will stop the study; if 1 or more CRs are observed, we will enter an additional 14 subjects for a 
total of 27 evaluable subjects.  The null hypothesis will be rejected if 4 or more CRs are observed in 27 subjects.  
Early discontinuation within the first 24 weeks or 6 cycles due to toxicity related to study drug are counted as 
non-response towards the primary efficacy endpoint. 

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As for the primary safety endpoint, treatment discontinuation rate has been reported to be 26% with the 
treatment with FCR,78 in contrast to 4% with the single-agent ibrutinib.55 Based on reported data, a treatment 
discontinuation rate <10% at 24 weeks would favor the improved safety and tolerability of the proposed 
regimen compared to conventional chemoimmunotherapy. We will use a Simon’s minimax two-stage design 
to test the null hypothesis (H0) that the treatment discontinuation rate is ≥30% against the alternative hypothesis 
(H1) that it is <30%.  In the first stage, up to 13 subjects will be enrolled: if 3 or more subjects discontinue 
treatment within 6 cycles due to intolerable side effects, further enrollment will be put on hold and we will 
request a review by the DSMB.  If 2 or fewer subjects discontinue treatment within 6 cycles among the first 13 
subjects, an additional 14 subjects will be enrolled for a total of 27 subjects. The null hypothesis will be rejected 
if 4 or fewer subjects discontinue treatment due to intolerable side effects among 27 subjects.  The above design 
for the primary safety endpoint has a power of 81% and a type I error of 0.05 if the true treatment discontinuation 
rate is 10%. 
 
9.4 
Statistical Methods 
 
The planned analyses will include descriptive statistics on the proportions of overall responses. 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, and, if appropriate, normal 
approximations.  The time to responses, 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. 
Methods based on multiple regression, analysis of variance, logistic regression and nonparametric regression 
will also be employed if deemed appropriate. 
 
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 >24h or intubation  
3.   Any grade 4 toxicity excluding  
• 
readily reversible metabolic or laboratory abnormalities 
• 
hematologic toxicities 
 
We anticipate the rate of these specified TRSAEs within the 6 months period (completion of primary endpoint) 
to be 15% or less. Following Geller et al. (2003, “Design of Early Trials in Stem Cell Transplantation: A Hybrid 
Frequentist-Bayesian Approach”),79 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 15% 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 alpha = 0.9, beta = 5.1. 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 the 6 months. 
 

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Number of  
subjects in the 
experiment 
Stop if the number of subjects 
who have developed any of 
the specified TRSAE’s 
reaches: 
≤ 6 
3 
≤ 11 
4 
≤ 16 
5 
≤ 21 
6 
≤ 26 
7 
≤ 32 
8 
 
 
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, we 
generated a study with 32 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 
Proportion of Stopped Studies 
4.4% 
17.9% 
41.3% 
66.1% 
84.2% 
Average number of subjects 
31.1 
28.9 
25.1 
20.6 
16.3 
Average number TRSAEs 
3.1 
4.3 
5.0 
5.2 
4.9 
 
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 15%, 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 (death that are 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 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 95%.  We take our prior distribution to be a 
beta distribution with parameters (α, β) = (0.3, 5.7). 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 
≤ 32 
4 
 
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, we 
generated a study with 32 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: 

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Probability of TRM = p 
0.03 
0.05 
0.07 
0.10 
0.15 
0.20 
Proportion of Stopped Studies 
4.7% 
14.2% 
27.7% 
49.6% 
78.5% 
   93.0% 
Average number of subjects 
31.1 
29.4 
27.1 
23.3 
17.1 
12.4 
Average number TRMs 
0.9 
1.5 
1.9 
2.3 
2.6 
2.5 
 
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 (CBC, chemistries) monitored for two months after study withdrawal for 
their safety.   
 
PI Decision: Study drug administration will be discontinued for adverse events as detailed in section 5.5. These 
subjects will be followed until resolution of the event and continue to be followed on protocol. Other off study 
criteria include: 
 
• 
Initiation of non-protocol treatment. 
o 
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  systemic 
therapy (i.e. breast cancer requiring surgery and adjuvant chemoradiation). If the new 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. 
• 
Significant progression of disease or a concomitant condition that would make the subject ineligible for 
further protocol participation. In selected cases, PI can decide if ibrutinib may be continued after 
progression until contingency plan for the next line of therapy is in place, and the benefit of treatment 
continuation outweighs potential risks.  
• 
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, 
consented to the Hematology Branch evaluation and treatment protocol (94-H-0010) for consideration 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 Inhye 
Ahn, M.D., and by the accountable and medically responsible investigator, Adrian Wiestner, M.D., Ph.D. 
 

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NHLBI’s 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 Safety and Monitoring Board 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 and fludarabine, 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.  We request review by the 
NHLBI DSMB since this is the first time ibrutinib and fludarabine are being used in combination in a clinical 
trial.  
 
Pharmacyclics, an AbbVie Company: Pharmacyclics, an AbbVie Company 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 medsciences@pcyc.com. 
 
10.1 
Assessment of Safety 
 
Definitions 
 
Adverse Event (AE):  Any untoward medical occurrence in a human subject, including any abnormal sign (e.g., 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s 
participation in the research, whether or not considered related to the subject’s participation in the research. 
 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by any 
of the following: 
 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms 
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization 
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will provide details 
about the action taken with respect to the test drug and about the patient’s outcome. 
 
Serious Adverse Event (SAE):   
 
• 
results in death; 
• 
is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
• 
results in in-patient hospitalization or prolongation of existing hospitalization; 
• 
results in a persistent or significant incapacity; 
• 
results in a congenital anomaly/birth defect; or 
• 
based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical 
or surgical intervention to prevent one of the other outcomes listed in this definition. 
 
Suspected adverse reaction: Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. A 

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suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
 
Serious event: An event is serious if it meets the definition of a serious adverse event (above) or if it requires 
immediate corrective action by a PI and/or IRB to protect the safety, welfare or rights of subjects. 
 
Unexpected adverse reaction: An adverse event or suspected adverse reaction is considered “unexpected” if it 
is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information described in 
the general investigational plan or elsewhere in the current application. "Unexpected”, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
 
Unanticipated Problem (UP):  Any incident, experience, or outcome that meets all of the following criteria: 
 
1. unexpected in terms of nature, severity, or frequency in relation to 
a. the research risks that are described in the IRB-approved research protocol and informed consent 
document; Investigator’s Brochure or other study documents; and 
b. the characteristics of the subject population being studied; and 
2. related or possibly related to participation in the research; and 
3. places subjects or others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. 
 
Unanticipated Problem that is not an Adverse Event:  An unanticipated problem that does not fit the definition 
of an adverse event, but which may, in the opinion of the investigator, involves risk to the subject, affect others 
in the research study, or significantly impact the integrity of research data.  For example, report occurrences of 
breaches of confidentiality, accidental destruction of study records, or unaccounted-for study drug. 
 
Asymptomatic Treatment-related Lymphocytosis: This event should also not be considered an AE. Subjects 
with treatment-related lymphocytosis should remain on study treatment and continue with all study-related 
procedures.  
 
Protocol Deviation (PD):  Any change, divergence, or departure from the IRB approved research protocol. 
 
Non-compliance: The failure to comply with applicable NIH HRPP policies, IRB requirements, or regulatory 
requirements for the protection of human research. Noncompliance may be further characterized as: 
 
1. Serious non-compliance: Non-compliance that: 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH HRPP 
d. Invalidates the study data 
 
2. Continuing non-compliance: Non-compliance that is recurring. An example may be a pattern of non-
compliance that suggests a likelihood that, absent an intervention, non-compliance will continue. Continuing 
noncompliance could also include a failure to respond to IRB requests to resolve previous allegations of non-
compliance. 
 
3. Minor (non-serious) non-compliance: Non-compliance that, is neither serious nor continuing. 
 

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Safety assessments will consist of monitoring and recording AEs and SAEs; measurements of protocol-
specified hematology, clinical chemistry, and other laboratory variables; measurement of protocol-specified 
vital signs; and other protocol-specified tests that are deemed critical to the safety evaluation of the study drug. 
 
10.1.1 
Severity 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) 
will be used for grading the severity (intensity) of non-hematologic AEs: 
 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, and not 
interfering with the patient’s daily activities 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or concern to the 
patient, and which may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly interrupt the 
patient’s usual daily activity, and require systemic drug therapy or other treatment 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in imminent danger 
of death 
Grade 5 (Death related to AE) – experiences which result in patient death 
 
Grading Scale for Hematologic Toxicity in CLL [Hallek 2008] 
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 (eg, < 20 x 109/L [20,000/μL]) was present 
pretreatment, in which case the patient is not evaluable for toxicity referable to platelet counts. 
3. 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. 
4. 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. 

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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. 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 SAE reporting timelines. Any congenital anomaly/birth defect 
noted in the infant must be reported as a serious adverse event. 
 
10.1.3 
AE and SAE causality assessments 
The following general guideline will be followed: 
                  Unrelated: 
Another cause of the adverse event is more plausible; a temporal sequence 
cannot be established with the onset of the adverse event 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 adverse 
event 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. 
Re-challenge with the investigational drug is not required. 
          Definitely Related: 
The adverse event is clearly related to use of the investigational product. 
 
10.2 
Documenting and Reporting of Adverse and Serious Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all patient evaluation time points during the study.  
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during questioning, or 
detected through physical examination, clinically significant laboratory test, or other means will be recorded in 
the patient’s medical record. 
 
10.3 
NHLBI-IRB and CD reporting 
10.3.1 Serious Events 
 Reports to the IRB and CD:   

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The PI must report serious UPs, and serious PDs, to the IRB and CD as soon as possible but not more than 
7 days after the PI first learns of the event. 
 
Reports to the IRB Chair and CD: 
The PI must report all SAEs that do not meet the definition of UP to the IRB chair and CD not more than 
14 days after the PI first learns of the event.  
 
Reports to Pharmacyclics LLC, an AbbVie Company: 
All serious adverse events and AE 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 ((408) 215-3500) to Pharmacyclics Drug Safety, or 
designee, within 24 hours of the event. Pharmacyclics may request follow-up and other additional 
information from the Sponsor Investigator. 
 
10.3.2 Non-serious Events   
Reports to the IRB and CD: 
The PI must report all UPs that are not serious to the IRB and CD, and PDs that are not serious to the IRB, 
not more than 14 days after the PI first learns of the event. 
 
10.3.3 Deaths 
The PI must report all deaths (that are not UPs) to the CD, and Pharmacyclics as soon as possible, but not 
more than 7 days after the PI first learns of the event.  
 
10.4 
Reports at the time of continuing IRB review:  
At continuing review, the PI will provide to the IRB a summary of:   
• 
All UPs 
• 
All PDs (except for those granted a waiver of reporting) 
• 
All AEs (except for those granted a waiver of reporting or any AEs occurred before the initiation of the 
study drugs) 
• 
If, while preparing the continuing review, the PI identifies a greater frequency or level of severity of 
expected adverse events than was previously identified in the protocol or investigational brochure (IB), 
these should be reported separately as a UP.  If such an observation occurs before the time of continuing 
IRB review, it should be reported to the IRB and CD as a UP in the time frames noted above, and 
summarized at the time of continuing review. 
 
Exclusions to data reporting: 
The following events will be captured only in the source documents and will not be reported to the IRB at the 
time of continuing review: 
• 
Laboratory values that do not meet the definition of AE listed in Section 9.2.2. 
• 
All grade 1 events listed as expected in the investigator’s brochure. 
• 
Study drug non-compliance will not be reported to the IRB unless patients are less than 80% 
compliant with study medications. 
 
10.4.1 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 

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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. 
 
Reporting for other malignancies  
Occurrences of any new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported throughout study participation, including duration of study treatment and 
during any protocol specified follow-up periods including post-progression follow-up for overall survival. 
 
10.4.2 Reporting Period and Reporting Requirements for SAEs  
NHLBI IRB: Please see section 10.3.1 above. 
 
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 24 hours in the case of death or life-threatening serious adverse events after the Investigator’s receipt 
of the information or becoming aware of the occurrence. All other SAEs will be reported no later than 24 
hours after 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.   
 
Drug Safety Contact Information 
Email: 
AEintakeCT@pcyc.com 
US Fax: 
1-408-215-3500 
 
The following may not be reported to the IRB immediately unless they meet the criteria of an SAE: 
• 
A standard procedure for protocol therapy administration. 
• 
The administration of blood or platelet transfusion. 
• 
A procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, sampling 
for laboratory tests, bone marrow sampling, pharmacokinetic or biomarker blood sampling). 
• 
Prolonged hospitalization for technical, practical, or social reasons in the absence of an adverse 
event 
• 
A procedure planned before entry into the study 
 
10.4.3 Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities. These events (regardless of seriousness) will be reported to Pharmacyclics Drug 
Safety per SAE reporting timelines.   
 
Major Hemorrhage 
Major hemorrhage is defined as any of the following: 
• 
Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*.  
• 
Any treatment-emergent serious adverse events of bleeding of any grade 
• 
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or higher 
AE per CTCAE v4. 
Events meeting the definition of major hemorrhage will be captured as an event of special interest according 
to above. 
 
10.5 
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 
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 

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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 Pharmacyclics, an AbbVie Company 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 
Pharmacyclics, an AbbVie Company 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. 
 
10.6 
Protocol Amendments 
Per the IST Agreement, any amendments to the Protocol or Informed Consent Form protocol must be sent to 
Pharmacyclics, an AbbVie Company 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 Pharmacyclics, an AbbVie Company a copy 
of a planned publication (abstract, poster, oral presentation or manuscript) prior to the submission thereof for 
publication or disclosure.  Pharmacyclics, an AbbVie Company 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 Pharmacyclics, an AbbVie Company comments 
or requests for additional information. 
 
10.7 
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 
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 

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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 This trend appears to be lost with age.  
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 previously untreated CLL: Ibrutinib is FDA-approved for the treatment of 
relapsed/refractory CLL and is therefore available outside of clinical trials. Furthermore, a substantial 
proportion of relapsed/refractory CLL is refractory to fludarabine-based regimens, which is typically given 
as a first-line drug. Thus, the combination of ibrutinib and short-course fludarabine is likely more effective 
in previously untreated CLL than in 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.14 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 protocol participation.   
 
Justification for Exclusion of pregnant women: There are no clinical studies that were done on pregnant 
women, and it is unknown whether ibrutinib or its 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.  

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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 AST and ALT levels < 3.0 × the institutional upper limit of normal (ULN) and 
a creatinine level ≤ 2.0 × the institutional ULN. 
 
Justification for Exclusion of Cognitively Impaired Subjects: Cognitively impaired and institutionalized 
persons will not participate in this study.  Subjects must be able to provide informed consent, and understand 
and comply with the treatment plan and follow-up. 
 
Inclusion of NIH Staff (At NIH CC only): NIH staff may voluntarily participate in this protocol. 
Recruitment, enrollment and compensation of NIH staff will be consistent with the Guidelines for the 
Inclusion of Staff in NIH Intramural Research Studies (April 2016) (HRPP SOP 14F, Appendix A; also 
Appendix C of this protocol) and NIH Policy Manual Chapter 2300-630-3 “Leave Policy for NIH 
Employees Participating in NIH Medical Research Studies” (HRPP SOP 14F, Appendix B).  
 
Recruitment: The study will be listed on the clinicaltrials.gov, Clinical Center research studies, and the 
National Heart, Lung and Blood Institute patient recruitment websites.  If recruitment goals are not met, a 
recruitment plan will be developed by the Clinical Center Office of Patient Recruitment.  
 
      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.   
 
Competition with other Branch protocols: This trial is the only active treatment protocol for treatment-
naïve CLL/SLL patients without deletion 17p. There will be little to no competition with existing branch 
protocols.  
 
11.2 
Risks and discomforts 
 
11.2.1 Risks related to Ibrutinib 
 
Bleeding-related events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib both with and without 
thrombocytopenia.  These include primarily minor hemorrhagic events such as contusion, epistaxis, and 
petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, intracranial 
hemorrhage and hematuria. Use of ibrutinib in subjects requiring other anticoagulants or medications that 
inhibit platelet function may increase the risk of bleeding. Subjects with congenital bleeding diathesis have 
not been studied. See Section 6.2.4 for guidance on concomitant use of anticoagulants, antiplatelet therapy 
and/or supplements. See Section 5.5 for guidance on ibrutinib management with surgeries or procedures. 
 
Cardiac Arrhythmias 
Atrial fibrillation and atrial flutter, and cases of ventricular tachyarrhythmia including some fatal events,  
have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac risk factors, 
hypertension, acute infections, and a previous history of cardiac arrhythmia. Subjects who develop 
arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea should be evaluated 
clinically, and if indicated, have an ECG performed.  For cardiac arrhythmia which persists, consider the 
risks and benefits of ibrutinib treatment and follow the protocol dose modification guidelines (see Section 
5.4). 
 

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Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were reported 
in subjects treated with ibrutinib. Subjects should be monitored for fever, weakness, or easy bruising and/or 
bleeding. 
 
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and combination 
therapy. Other frequently reported gastrointestinal events include nausea, vomiting, and constipation. These 
events are rarely severe. Should symptoms be severe or prolonged follow the protocol dose modification 
guidelines (see Section 5.4). 
 
Infections 
Infections (including sepsis, bacterial, viral, or fungal infections) 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. Subjects should be monitored for signs and symptoms (fever, chills, 
weakness, confusion, vomiting and jaundice) 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 tumor lysis syndrome are those with 
comorbidities and/or risk factors such as high tumor burden prior to treatment, increased uric acid 
(hyperuricemia), elevated lactate dehydrogenase (LDH), bulky disease at baseline, and pre‐existing kidney 
abnormalities. 
 
Liver Failure 
Rare cases of liver failure have been reported in patients treated with ibrutinib. 
 
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 ibrutinib. 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 (eg, dyspnea, cough or pyrexia) and treated symptomatically, 
including interruption of the suspected agent as appropriate. Should symptoms develop 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. 
 

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Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥50% increase from baseline 
and an absolute count 5000/mc µL), often associated with reduction of lymphadenopathy, has been 
observed in most subjects with CLL/SLL treated with ibrutinib as a single agent. This effect has also been 
observed in some subjects with 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 few weeks of ibrutinib 
therapy (median time 1.1 weeks) and typically resolves within a median of 8.0 weeks in subjects with MCL 
and 14 weeks in subjects with CLL/SLL. This pharmacodynamic effect was less prominent or not observed 
in other indications. 
 
A large increase in the number of circulating lymphocytes (eg, >400,000/µL) has been observed in some 
subjects. Lymphocytosis was not commonly observed in subjects with Waldenström’s macroglobulinemia 
treated with ibrutinib. Lymphocytosis appeared to occur in lower incidence and at lesser magnitude in 
subjects with CLL/SLL receiving ibrutinib in combination with chemoimmunotherapy.  
 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects for new 
onset of hypertension or hypertension that is not adequately controlled after starting ibrutinib. Adjust 
existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. 
 
Potential for Drug-Drug Interactions: Ibrutinib is primarily metabolized by CYP3A.  
 
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 patients with B-cell malignancies, co-administration of voriconazole increased 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 patients treated with mild and/or moderate CYP3A inhibitors when compared with the 
ibrutinib exposure in 76 patients 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 patients with B-cell malignancies, co-administration of the CYP3A inhibitor erythromycin increased 
Cmax and AUC by 3.4-fold and 3.0-fold, respectively. If a moderate CYP3A inhibitor (eg, fluconazole, 
erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, 
imatinib, verapamil, amiodarone, dronedarone) is indicated in patients with B-cell malignancies, reduce the 
ibrutinib dose to 280 mg for the duration of the inhibitor use. or as per recommended dose modifications 
described in the specific clinical study protocol. No ibrutinib dose modifications for moderate inhibitors 
are required in patients with cGVHD dosed with ibrutinib 420 mg. 
 

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No dose adjustment is required in combination with mild inhibitors. Monitor patient 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. 
 
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 toward CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A4/5 and does not display time--dependent CYP 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 CYP isoenzymes in vitro. 
Therefore, it is unlikely that ibrutinib has any clinically relevant drug-drug interactions with drugs that may 
be metabolized by the CYP enzymes. 
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. 
 
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. 
 
11.2.2 Risks related to blood draws: 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.  
 
11.2.3 Risks related to CT Scan:  CT (computed tomography), sometimes called CAT scan, 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 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 1.3 rem of radiation 
annually, which is below the guideline of 5 rem (or 0.5 rem in children) per year allowed for research 
subjects by the NIH Radiation Safety Committee.  All female subjects will receive pregnancy testing prior 
to radiation exposure. 
 

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11.2.4 Related to pregnancy and nursing mothers:  There are no clinical studies in pregnant women, and 
it is unknown whether ibrutinib or its metabolites are excreted in human milk. Men and women of child-
bearing potential must use highly effective contraceptive (eg, condoms, implants, injectables, combined 
oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) protection 
while on study and for 90 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. 
 
11.2.5 Related to central line placement (only when indicated): A catheter may be placed in a large vein 
of the neck, chest, or arm using local anesthetic. Patients will sign a separate consent for the placement 
procedure. Only trained experienced staff will place the line in order to minimize these procedure related 
risks. The risks from the procedure are low; they include bleeding, bruising, or infection at the site of 
insertion. Some patient may experience a vasovagal reaction (lightheadedness, or, rarely, fainting due to 
temporary lowering of blood pressure).  Very rarely (less than 1% of the time), the line placement may nick 
the lung causing it to collapse during line insertion. If the lung collapses, a tube may have to be inserted 
into the chest and remain in place until the lung re-expands. Because of this risk, patients will have a chest 
x-ray following the procedure to make sure the line is in the correct place and that the lung is not collapsed. 
Once placed, the line will remain in place until drug administration is complete. 
 
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. 
 
11.2.7 Risks related to transfusions: Some risks with the transfusion with blood and /or blood products 
include fever or allergic reactions. These risks are uncommon and are usually mild, but on rare occasions 
may be severe or life threatening. Extremely rare risks include infections with viruses, such as hepatitis or 
HIV or serious incompatibility reactions.  
 
11.3 
Risks in Relation to Benefit 
 
The benefits to the adult patient could be a reduction or a disappearance 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. Therefore, this 
research involves greater than minimal risk to subjects with the prospect of direct benefit (45 CFR 46.102). 
 
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 Process as described in MAS Policy M77-2, 45 CFR 46.117 (b) (2), and 21 

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CFR50.27 (b) (a)0. The summary that will be used is the English version of the extant IRB approved consent 
document.  
 
We request prospective IRB approval of the use of the short form for up to a maximum of 5 research participants 
in a given language and will notify the IRB at the time of continuing review of the frequency of the use of the 
Short Form.  Should we reach the threshold of 5, we will notify the IRB of the need for an additional use of the 
Short Form and that we will have that consent document translated into the given inherent language. 
 
Informed consent process for NIH employees : If the individual requesting to participate is a co-worker, the 
consent from the employee (co-worker) will not be obtained by the employee’s direct supervisor but by another 
research staff member approved for obtaining informed consent and who is also not a co-worker. Neither 
participation nor refusal to participate as a subject in this protocol will have an effect, either beneficial or 
adverse, on the participant’s employment or position at NIH. However, all subjects will be made aware that 
there are limits to these protections. The PI, through the consenting staff member will make the “NIH 
Information Sheet on Staff Research Participation” available to the NIH staff who are considering enrolling in 
research. (HRPP SOP 14F, Appendix A; also in Appendix C of the protocol). In addition, all NIH staff that 
choose to participate in this study can access HRPP SOP 14F, Appendix B (NIH Policy Manual Chapter 2300-
630-3 “Leave Policy for NIH Employees Participating in NIH Medical Research Studies”).  
 
11.5 
Conflict of Interest 
 
Pharmacyclics, an AbbVie Company is providing ibrutinib for this study to NIH without charge. No NIH 
ivestigator involved in this study receives any payment or other benefits from Pharmacyclics, an AbbVie 
Company. 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 Pharmacyclics, an AbbVie 
Company. 
 
 
12.0 
PHARMACEUTICALS  
 
12.1 
Ibrutinib48 
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, hard gelatin capsule containing 140 
mg of ibrutinib.  The capsules are packaged in 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. The recommended storage condition for ibrutinib is room 
temperature (15 to 25°C).  
 

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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 monthly visit, only enough ibrutinib for 1 cycle should be dispensed.  After cycle 6 when follow 
ups are done every 3 months, only enough ibrutinib until the next follow up visit should 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 redispensed.  
Ibrutinib 420 mg (3 capsules at 140-mg per capsule) is intended to be administered orally once daily with a 
glass of water (avoid GRAPEFRUIT JUICE and SEVILLE ORANGES). 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 no specific experience in the management of ibrutinib overdose in patients. 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. One healthy subject experienced 
reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg. Subjects who ingested 
more than the recommended dosage should be closely monitored and given appropriate supportive treatment. 
Refer to Section 10.4.1 for further information regarding AE reporting. 
Supply: The drug product ibrutinib is manufactured by Pharmatek Laboratories, Inc (San Diego, CA) or Aptuit 
(Kansas City, MO). 
Shipping:  
National Institutes of Health 
PHARM DEV SVC, Room 1C230 
10 Center Drive, MSC 1196, Building 10 
Bethesda, Maryland 20892-1196 
Shipping Designee Name:  Hope Decederfelt, RPh 
Shipping Designee Phone No: (301) 402-8153 
Shipping Designee FAX No:  (301) 402-3268 
Shipping Designee e-mail: HDecederfe@cc.nih.gov 
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 
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. 

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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. 
 
Supply: commercially available. 
 
12.3 
Off-Label Use of Drugs 
 
Ibrutinib and fludarabine will be used in this study beyond what is indicated in their Package Inserts.  Ibrutinib 
and fludarabine are approved by the FDA for the treatment of patients with CLL regardless of prior treatment 
status; however, this protocol will be investigating ibrutinib and fludarabine on subjects who are treatment 
naive.  The use of this drug meets the requirements for an exemption from the IND regulations, 21 CFR 312, 
specifically: 
1. The investigational drug is lawfully marketed in the United States. 
2. The investigation is not intended to be reported to the FDA as a well-controlled study in support of a new 
indication for use of the drug product. 
3. The investigation is not intended to support a significant change in advertising to an existing lawfully 
marketed prescription drug product. 
4. The investigation does not involve a route of administration or dosage level or use in a patient population 
or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product.   
5. The investigation will be conducted in compliance with the requirements for institutional review set forth 
in FDA regulations 21 CFR 56, and requirements for informed consent as set forth in FDA regulations 
21 CFR 50. 
6. The investigation will be conducted in compliance with FDA regulations 21 CFR 312.7:  Promotion and 
charging for investigational drugs. 
 
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 and Pharmacyclics, an 
AbbVie Company.  Disposition of all unused boxes of study drug will be carried out according to instructions 
provided by the sponsor and/or Pharmacyclics, an AbbVie Company at the end of the study after drug 
accountability is performed by the study monitor. 
 
 

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induce defective LFA-1-directed T-cell motility by altering Rho GTPase signaling that is reversible with 
lenalidomide. Blood 2013;121:2704-14. 
70. 
Ysebaert L, Gross E, Kuhlein E, et al. Immune recovery after fludarabine-cyclophosphamide-rituximab 
treatment in B-chronic lymphocytic leukemia: implication for maintenance immunotherapy. Leukemia 
2010;24:1310-6. 
71. 
Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide 
compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup 
Trial E2997. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2007;25:793-8. 
72. 
Kornblit B, Maloney DG, Storb R, et al. Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as 
conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Biol 
Blood Marrow Transplant 2013;19:1340-7. 
73. 
Khouri IF, Wei W, Korbling M, et al. BFR (bendamustine, fludarabine, and rituximab) allogeneic 
conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood 
2014;124:2306-12. 
74. 
Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell 
lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an 
anti-CD19 chimeric antigen receptor. J Clin Oncol 2015;33:540-9. 
75. 
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen 
receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. 
Lancet 2015;385:517-28. 
76. 
Beyer M, Kochanek M, Darabi K, et al. Reduced frequencies and suppressive function of CD4+CD25hi 
regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 
2005;106:2018-25. 
77. 
Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, 
response assessment, and supportive management of CLL. Blood 2018;131:2745-60. 
78. 
Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of 
fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2005;23:4079-88. 
79. 
Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment 
in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-
HD4 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2012;30:2946-55. 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
54
APPENDIX A:  Schedule of Events  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day/NAME:  
Scre
enin
g 
Bas
elin
e 
C1
& 
2 
C3 &4 
C5
&6 
Follow up 
every 3 
months 
Response 
Assessment 
After cycle 6 
Response 
Assessment 
Annually 
At 
progression  
Days (Plus/Minus) 
N/A 
±5 
±5 
±5 
 
 
 
 
 
±5 
±14 
±30 
±30 
N/A 
Day of the cycle 
N/A 
N/A 
D1 
D1 
D
2 
D
3 
D
4 
D5 
D14 
D21 
D1 
N/A 
N/A 
N/A 
N/A 
NIH visit 
X 
X 
X 
X 
X 
X 
X 
X 
home 
X 
X 
X 
X 
 X 
Clinical 
  
  
 
 
 
 
 
 
 
  
  
 
  
  
Consent 
  
X  
 
 
 
 
 
 
 
  
  
  
  
  
History, ECOG PS 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X  
Physical Exam  
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X  
Medication Review 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X  
Specific Labs/Other Tests 
  
  
 
 
 
 
 
 
 
  
  
 
  
  
HLA Typing (as clinically indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X  
Acute Care & Mineral Panel 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X  
Tot. protein, Uric Acid, LDH  
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X  
Hepatic Panel 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X  
Reticulocyte Count 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X  
PT, PTT 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
SPEP with IFE 
 
X 
 
 
 
 
 
 
 
  
 
 
 
[R] 
SFL with qIG 
 
X 
 
 
 
 
 
 
 
  
X 
X 
X 
CRP 
 
X 
 
 
 
 
 
 
 
 
[R] 
β2  Microglobulin 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
DAT 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
Iron studies (ferritin, transferrin, iron) 
X 
  
 
 
 
 
 
 
 
 
  
 
  
  
Folate, Vit B12 
X 
  
 
 
 
 
 
 
 
  
 
  
  
Viral Studies (HIV, Hepatitis)  
X 
  
 
 
 
 
 
 
 
  
 
  
  
Pregnancy test 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
TBNK# 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
IGHV mutation analysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
[R] 
Flow CLL (w/in 3 mo of starting) 
X 
 
 
 
 
 
 
 
X 
X 
X  
CT Neck, CAP (w/in 3 mo of starting) 
X 
 
X 
 
 
 
 
 
X 
X 
X 
Bone Marrow( w/in 3mo of starting) 
 
X 
 
 
 
 
 
 
 
 
 
X 
[R] ** 
[R] 
CLL/FISH (w/in 3 mo of starting) 
X 
 
 
 
 
 
 
 
 
[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] 
[R] 
[R]  
Research blood 
 
X 
X 
X 
 
 
 
[R] 
 
[R] 
X 
X 
X 
X  

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
55
Footnotes for Schedule of Events: 
A 
If C1D1 labs were collected within 5 days for screening or baseline studies, the study team may decide not to repeat the labs. 
*  
Up to 3 lymph node biopsy can be performed in consented patients. 
** 
Bone marrow biopsy may be done to confirm complete response (optional). 
# 
TBNK is performed baseline, before C3 and at response assessments (after cycle 6 and annually thereafter). 
[R] Optional, drawn at discretion of clinical team 
X  Mandated 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
56
APPENDIX   B:  
NHLBI HEMATOLOGY BRANCH LABORATORY RESEARCH STUDIES -2/5/2013 
 
DESCRIPTION OF LABORATORY STUDY BY BRANCH SECTION 
Does this test 
pose a greater 
than minimal 
risk to 
pediatric 
subjects per 45 
CFR 46.404? 
Does this test 
pose a 
greater than 
minimal risk 
to healthy 
pediatric 
donors per 45 
CFR 46.404? 
 
 
A 
Stem Cell Allotransplantation Section (Dr. A. John Barrett) 
 
 
A.1 
Measurement of lymphocyte function and immune responses directed toward 
allogeneic tissues, malignant cells, and infectious agents.  Assay of a variety of 
antigens, including standard proliferation, cytotoxicity, and intracellular cytokine  
detection including GVHD predictive markers. Measurement of antigen-specific 
responses including employment of tetramers, ELISPOT technique, gene 
amplification-based assays, and flow cytometry.  Selection of cells using 
immunomagnetic beads or flow cytometry.  Culture, expansion, and selection of 
cells. Surface marker analysis of PB MC using flow cytometry. Cytokine/chemokine 
analysis of plasma/serum samples using ELISA and/or Luminex techniques. 
 
No 
No 
A.2 
Generation of cell lines for the study of immune cell interactions with other cells.  
Transformation of B-lymphocytes using Epstein-Barr virus.  Derivation of malignant 
cell lines from patient leukemic or solid tumor samples. 
No 
No 
A.3 
Infection of cells and cell lines with recombinant genes to ascertain the effects of 
expressed molecules on immune responses and on growth and development. 
Transfection of cell lines with specific molecules to study antigen-specific responses. 
No 
No 
A.4 
Assays of peripheral blood and bone marrow progenitor cells including primitive and 
late erythroid progenitor-derived colonies, myelomonocytic colonies, and primitive 
multi- potential progenitor-derived colonies. 
No 
No 
A.5 
Injection of human cells into experimental animals to study the immune system and 
the growth of normal and malignant cells under varying conditions. 
No 
No 
A.6 
Testing of selection methods, cell isolation, and cell expansion leading to the 
development of new cell-based therapies requiring scale-up for clinical application. 
No 
No 
A.7 
Identification of individual T cell clones by their T cell receptor sequence. 
No 
No 
A.8 
Measurement of tumor and tissue specific antigens in cells of subjects and donors by 
mRNA,protein, or peptide expression in cells or fluids. 
No 
No 
A.9 
Laser capture micro dissection of cells from biopsies for GVHD to determine 
clonotypes. 
No 
No 
A.10 
DNA and RNA typing of genes that control immune responses in lymphocytes. 
No 
No 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
57
A.11 
Microassay studies utilizing cellular DNA, cDNA, and RNA for neoplasia and host-
tumor interactions. 
No 
No 
 
 
B 
Molecular Hematopoiesis  Section  (Dr. Cynthia Dunbar)  
 
 
B.1 
Flow cytometric analysis of cell surface and cytoplasmic proteins, including cell 
adhesion molecules, putative retroviral receptors, and markers of differentiation, 
using bone marrow and mobilized peripheral blood cells. 
No 
No 
B.2 
Hematopoietic progenitor-derived colony ascertainment in vitro (as described above), 
and engraftment of immunodeficient mice for detection of human stem cell number 
and function. 
No 
No 
B.3 
Testing ability of hematopoietic progenitor cells to be transduced with retroviral, 
lentiviral, and novel gene transfer vectors in vitro. 
No 
No 
B.4 
Reprogramming of adult mature cells, including skin fibroblasts and blood cells, into 
induced pluripotent stem cells in vitro. 
No 
No 
 
 
C 
Cell Biology Section (Dr. Neal Young)  
 
 
C.1 
Studies of blood and bone marrow hematopoietic progenitor numbers, including 
early and late erythroid progenitors, myelomonocytic progenitors, and multi-potential 
progenitor cells.  In addition, bone marrow may be placed in long-term bone marrow 
culture to assess the function of stroma and stem cells and to assay more primitive 
progenitors, as well as organelle culture.  Whole or selected bone marrow 
populations are cultured short-term for CD34 cell expansion. 
No 
No 
C.2 
Assays of apoptosis in hematopoietic cells and their progeny, using flow cytometric 
methods such as annexin and caspase-3 staining, propidium iodide uptake, and 
mitochondrial permeability tests. 
No 
No 
C.3 
Separation and functional study of cell populations characteristic of paroxysmal 
nocturnal hemoglobinuria, identified by absence of glycosylphosphatidylinositol 
anchored proteins. 
No 
No 
C.4 
Studies of mutation rates in hematopoietic cells and in buccal mucosa cells, using 
conventional hypoxanthine phosphoribosyltransferase activity functional assays, 
sequencing of mitochondrial DNA after specific gene amplification, and 
measurement of GPI-anchored deficient cells in blood and bone marrow. 
No 
No 
C.5 
Assays of immune function of T-cells, including intracellular cytokine staining, 
ELISPOT, semiquantitative gene amplification for gamma-interferon, tumor necrosis 
factor, interleukin-2, and other cytokines, and functional assessment in co-culture 
using specific neutralizing monoclonal antibodies.  In addition, peripheral blood 
lymphocytes are subjected to spectratyping for CDR3 size distribution as well as 
nucleotide sequence of CDR3 peaks obtained. 
No 
No 
C.6 
Studies of engraftment of human normal and diseased bone marrow and peripheral 
blood in immunodeficient mice in order to determine the presence of hematopoietic 
repopulating stem cells as well as functional differences among selected populations. 
No 
No 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
58
C.7 
Flow cytometric analysis of blood and bone marrow for lymphocyte phenotype, 
especially for evidence of activation of lymphocytes, for markers of apoptosis, and 
for antigens associated with primitive and mature hematopoietic cell populations. 
No 
No 
C.8 
Flow cytometric analysis of blood and bone marrow for hematopoietic stem cell 
progenitors and CD34 positive cells. 
No 
No 
C.9 
Studies of chromosomal instability in myelopdysplastic syndromes including BM 
cell and CD34 cell response to PAS crosslinking and examination of the cytotoxic 
effect of lymphocytes to the abnormal clone of cells. 
No 
No 
C.10 
Surface Enhanced Laser/Desorption Ionization (SELDI)  time-of-flight mass 
spectrometry (Ciphergen)  (proteomics methodology). 
No 
No 
C.11 
Mitochondrial DNA (mtDNA) sequence heterogeneity. 
No 
No 
C.12 
Measurement of EBV viral load. 
No 
No 
C.13 
Measurement of EBV LMP-1 via RT-PCR for LMP-1 RNA or flow cytometry for 
LMP-1. 
No 
No 
C.14 
Outgrowth assay of EBV transformed B cells. 
No 
No 
C.15 
Quantification of serum chemokines and cytokines (e.g. SDF-1, IL-10, IL-6, CXCR4, 
CXCL12). 
No 
No 
C.16 
Quantification of EBV cytotoxic T cells (tetramerstaining). 
No 
No 
C.17 
Telomere length measurement by Southern blot, Q-PCR, flow-fish, in situ 
hybridization and STELA 
No 
No 
C.18 
Telomere repair complex gene mutations by nucleotide sequencing of some or all of 
the following:  DKC1 ,TERC, TERT, SBDS, NOp10 , NHP2. 
No 
No 
C.19 
Analysis of  inflammatory markers and/or bacterial, viral, fungal or protozoal 
elements in plasma or serum using molecular, colorimetric, enzymatic, flow 
cytometric or other assays in subjects receiving immunosuppressive therapy, 
chemotherapy and/or bone marrow transplantation. 
No 
No 
C.20 
Confocal microscopic imaging of bone marrow. 
No 
No 
C.21 
Characterization of intracellular signaling proteins by cell permeabilization and flow 
cytometry, and quantitative immunoblots. 
No 
No 
C.22 
Assays for chromosomal aneuploidy by florescence in situ hybridization (FISH) and 
other molecular techniques. 
No 
No 
C.23 
Conversion of human dermal fibroblasts into hematopoietic progenitors using Oct4 
transfection. 
No 
No 
 
 
D 
Virus Discovery Section (Dr. Neal Young) THESE ASSAYS WILL NOT BE 
PERFORMED ON SAMPLES FROM HEALTHY PEDIATRIC DONORS 
 
 
D.1 
Assays of serum, blood cells, and bone marrow cells for B19 parvovirus and possible 
B19  variants using gene amplification, cell culture, and hematopoietic colony 
inhibition assays. 
No 
N/A 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
59
D.2 
Assays of blood, bone marrow, liver, and other tissues for potentially novel viruses, 
using a variety of techniques including RNA and DNA assays, differential display, 
gene amplification with conserved and random primers, cell culture assays, 
immunohistochemical methods, and inoculation of mice, rabbits, and monkeys, as 
well as antibody measurements. 
No 
N/A 
D.3 
Assays of blood, bone marrow, and liver for known viruses, including herpesviruses 
such as cytomegalovirus, human herpesviruses 6, 7, and 8, enteric viruses such as A-
6, circiviruses, and parvoviruses, using assays as in (2). 
No 
N/A 
D.4 
Spectra-typing of blood cells to determine response to known or putative viral 
infections. 
No 
N/A 
D.5 
HLA typing or subtyping to determine risk factors/determinants for hepatitis-AA 
studies. 
No 
N/A 
D.6 
Cytotoxic lymphocyte assays with intracellular cytokine measurement for 
determining anti-viral response and lymphocyte cloning to obtain clones with 
specific antiviral activity. 
No 
N/A 
 
 
E 
Solid Tumor Section (Dr. Richard Childs) 
 
 
E.1 
Cr51 cytotoxicity assay to evaluating killing of patient tumor cells by patient NK cell 
clones and T-cells. 
No 
No 
E.2 
ELISA for IL-12  maturity of DC's made from subjects monocytes. 
No 
No 
E.3 
ELISA for IFN ã to evaluate specificity of CTL clones. 
No 
No 
E.4 
H thymidine uptake to evaluate proliferation potential of antigen specific T-cells. 
No 
No 
E.5 
PCR of STR to assess chimerism status of cellular subsets grown in-vitro or retrieved 
from subjects post-transplant. 
No 
No 
E.6 
Flow sorting of PBL and/or tissue samples to evaluate chimerism of different subsets. 
No 
No 
E.7 
Surface marker analysis of peripheral blood mononuclear cells using flow cytometry. 
No 
No 
E.8 
cDNA expression arrays to evaluate T-cells expression/gene patterns in subjects with 
GVHD and a GVT effect. 
No 
No 
E.9 
Geno typing of tumor or tissue samples by high density cDNA arrays. 
No 
No 
E.10 
VHL mutation analysis on kidney cancer tissue. 
No 
No 
E.11 
Transduction of dendritic and tissue cells with tumor antigens using plasmids, viral 
vectors and hybrid fusions. 
No 
No 
E.12 
Lasar capture microdissection of cells from tumor biopsies and tissue samples  to 
determine origin (donor vs patient). 
No 
No 
E.13 
Quantification of polyoma virus BK exposure by serology and PCR in stem cell 
transplant donors and recipients from blood and urine samples. 
No 
No 
E.14 
Quantification of polyoma virus BK specific T cells in stem cell transplant donors 
and recipients from peripheral blood samples. 
No 
No 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
60
 
 
 
E.15 
Determination of origin of neovasculature endothelial cells in tumor and tissue 
samples obtained from subjects post-transplant. 
No 
No 
E.16 
Quantification of lymphocyte subsets CD34 progenitors and endovasculator 
progenitors in G-CSF mobilized peripheral cell allografts. 
No 
No 
E.17 
Testing for polyoma virus BK latency in CD34 progenitors, B cells and T cells in the 
G-CSF mobilized peripheral cell allografts. 
No 
No 
E.18 
Determination of etiology of membraneous nephropathy using serum from subjects. 
No 
No 
E.19 
Serum Proteomic patterns analysis to diagnose complications related to allogeneic 
transplantation. 
No 
No 
E.20 
Determine cell origin (donor vs patient) of tissue samples using IHC, IF, sorting, and 
FISH. 
No 
No 
 
 
F 
Lymphoid Malignancies Section (Dr. Adrian Wiestner) 
 
 
F.1 
Culture of cells from research subjects to investigate molecular disease mechanisms, 
model host tumor interactions, and to test effect of drugs on cell survival and cellular 
functions. 
No 
No 
F.2 
Generation of stable cell lines for the study of hematologic malignancies. 
No 
No 
F.3 
Modifications of cells using standard expression systems or biologic molecules, e.g. 
interfering RNA, to investigate the effects of candidate genes on cellular functions. 
 
 
F.4 
Identification and monitoring of B or T cell populations as identified by flow 
cytometry and by their B cell or T cell receptor expression. 
No 
No 
F.5 
Measurement of gene expression in cells or tissues. Techniques frequently used 
include gene expression profiling on microarrays, quantitative RT-PCR, Western 
blotting, flow cytometry and ELISA assays. 
No 
No 
F.6 
Analysis of chromosomal abnormalities or mutations in malignant cells and non-
malignant cells including FISH technology and DNA sequencing. 
No 
No 
F.7 
Assays of immune function of B-cells and T-cells, including intracellular cytokine 
staining, ELISPOT, quantitative RT-PCR for cytokines or other immune regulatory 
genes. 
No 
No 
F.8 
Analysis of antibody specificities in serum and antigen specificity of the B-cell 
receptor on cells. Techniques may include expression of antibodies in phage display 
systems, generation of antibodies in cell culture systems and use of such antibodies to 
screen for cognate antigens. 
No 
No 
F.9 
Transplantation of human cells into mice (xenograft model) to study disease biology 
and to investigate the effect of experimental therapy. 
No 
No 
F.10 
Measurements of drug concentrations, biologic molecules and disease markers in 
blood, serum, and plasma. 
No 
No 

15-H-0172 
Inhye Ahn, M.D. 
March 26, 2019 (Amendment L) 
61
APPENDIX C: NIH INFORMATION SHEET ON STAFF RESEARCH PARTICIPATION (APRIL 
2016) 
 
As an NIH employee, contractor, Special Volunteer, Guest Researcher, or trainee, you may participate in 
intramural research studies unless it is prohibited by your Institute or Center (IC), or if you are excluded by 
the criteria of the protocol in which you want to enroll. The inclusion of NIH staff in a particular protocol 
must also be approved by the IRB. You may be motivated by altruism, a commitment to research in your 
own or related fields, or want access to clinical trials of potential direct therapeutic benefit. When deciding, 
you should make an informed decision about participation. This information sheet offers some points to 
consider for NIH staff who are considering research participation at NIH. 
 
First, similar to any individual who is considering research participation, you should seek adequate 
information about the study purpose, what is required of you in terms of procedures, interventions and time, 
and the potential risks and benefits of participation. For more information, see the NIH Clinical Center’s 
public website “Are Clinical Studies for You?” at http://www.cc.nih.gov/participate/studies.shtml. When 
you are thinking about participation in a research study that is being conducted by your supervisor, or 
others with whom you work closely in your laboratory, branch, or unit, you should consider some 
additional factors: 
 
A. Possible bias: Are you confident that you can be unbiased about reporting answers, side effects, or other 
information that could influence the study outcome or risk to you? 
 
B. Confidentiality: Has the principal investigator (PI) spoken about what information will be collected 
from you as part of the study? Has the PI discussed what information will be available to those within, and 
outside, the study team? If applicable, are you comfortable sharing your medical history (including, for 
example, mental health history or STDs) and your social history (e.g. substance use) with study 
investigators who may be your coworkers, or with the possibility of them discovering something about 
your health during the study (e.g. pregnancy status or a new diagnosis)? Although every effort will be made 
to protect your information and keep it private and confidential, your information may, depending on the 
nature of the protocol, become available in medical records or to authorized users outside of the study team. 
Discuss any concerns with the PI. 
 
C. Pressure: Do you perceive any pressure or expectations from your supervisor or colleagues regarding 
participation? Could that pressure influence your decision or make it difficult for you to choose whether or 
not to participate? Remember that it is your choice whether or not to participate and that your decision to 
participate or not should not have an effect, either beneficial or adverse, on your position at NIH.