Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

PRIMARY OBJECTIVES:

I. To evaluate the ability of Ibrutinib-based induction therapy to prolong progression free
survival (PFS) compared to standard fludarabine phosphate, cyclophosphamide, and rituximab
(FCR) chemoimmunotherapy for younger patients with chronic lymphocytic leukemia (CLL).

SECONDARY OBJECTIVES:

I. Evaluate overall survival (OS) of patients based on treatment arm. II. Monitor and assess
toxicity of treatment with Ibrutinib-based induction relative to standard FCR chemotherapy.

III. To compare quality of life (QOL) in CLL patients during the first 6 months of treatment
among patients receiving Ibrutinib-based induction therapy relative to standard FCR
chemoimmunotherapy.

IV. To compare QOL over the long-term in CLL patients receiving continuous therapy using
Ibrutinib to that of CLL patients who completed FCR therapy.

V. Determine the effect of pretreatment clinical and biological characteristics (e.g. disease
stage, immunoglobulin heavy chain variable region gene [IGHV] mutation status, fluorescent in
situ hybridization [FISH]) on clinical outcomes (e.g. complete response, PFS) of the
different arms.

VI. Determine if the minimal residual disease (MRD) status as assessed by flow cytometry at
different time points during and after treatment is an effective surrogate marker for
prolonged PFS and overall survival.

VII. Compare the genetic abnormalities and dynamics of intra-clonal architecture of CLL
patients before and after treatment with chemoimmunotherapy (CIT) and non-CIT approaches and
explore relationships with treatment resistance.

VIII. Explore the effects of FCR and Ibrutinib-based therapy on T-cell immune function.

IX. Conduct confirmatory validation genotyping of single nucleotide polymorphisms (SNPs)
associated with the efficacy and toxicity of fludarabine-based therapy as in a prior Eastern
Cooperative Oncology Group (ECOG) genome-wide association study (GWAS) analysis in the E2997
trial.

X. Evaluate the ability of prognostic model that incorporates clinical and biologic
characters to predict a response to therapy and clinical outcome (PFS, OS).

XI. Evaluate signaling networks downstream of the B-cell receptor in patients receiving
Ibrutinib-based therapy.

XII. Collect relapse samples to study mechanisms of resistance to both FCR and
Ibrutinib-based therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Beginning course
2, patients also receive rituximab intravenously (IV) over 4 hours on day 1 (days 1 and 2 of
course 2 only). Treatment repeats every 28 days for 7 courses. In the absence of disease
progression, patients may continue ibrutinib PO QD.

ARM B: Patients receive rituximab as seen in Arm A and fludarabine phosphate IV over 30
minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days
for 6 courses.

After completion of study treatment, patients are followed up for 10 years.

Inclusion Criteria:

- Diagnosis of CLL according to the National Cancer Institute (NCI)/Internal Workshop on
Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL)
according to the World Health Organization (WHO) criteria; this includes previous
documentation of:

- Biopsy-proven small lymphocytic lymphoma or

- Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the
following:

- Peripheral blood lymphocyte count of greater than 5 x 10^9/L

- Immunophenotype consistent with CLL defined as:

- The predominant population of lymphocytes share both B-cell antigens
(cluster of differentiation [CD]19, CD20 [typically dim expression], or
CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3,
CD2, etc)

- Clonality as evidenced by kappa or lambda light chain restriction
(typically dim immunoglobulin expression)

- Negative FISH analysis for t(11;14)(immunoglobulin heavy locus [IgH]/cyclin D1
[CCND1]) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative
immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g.
marrow aspirate or lymph node biopsy)

- No prior chemotherapy, Bruton's tyrosine kinase (BTK) inhibitor therapy, or monoclonal
anti-body therapy for treatment of CLL or SLL

- Has met at least one of the following indications for treatment:

- Evidence of progressive marrow failure as manifested by the development of
worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets <
100 x 10^9/L)

- Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly

- One or more of the following disease-related symptoms:

- Weight loss >= 10% within the previous 6 months

- Grade 2 or 3 fatigue attributed to CLL

- Fevers > 100.5 Fahrenheit (F) for 2 weeks without evidence of infection

- Clinically significant night sweats without evidence of infection

- Progressive lymphocytosis (not due to the effects of corticosteroids) with an
increase of > 50% over a two-month period or an anticipated doubling time of less
than six months

- ECOG performance status between 0-2

- Life expectancy of >= 12 months

- Ability to tolerate FCR based therapy

- No deletion of 17p13 on cytogenetic analysis by FISH

- Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault
formula

- Total bilirubin =< 2.5 x upper limit of normal (ULN) unless due to Gilbert's disease;
for those with a total bilirubin > 2.5 x ULN, a direct bilirubin should be performed
and must be < 1.5 mg/dL for Gilbert's to be diagnosed; if value is higher due to
hepatic involvement by CLL, patient is eligible

- Serum glutamic oxaloacetic transaminase (SGOT) aspartate transaminase (AST)/serum
glutamate-pyruvate transaminase (SGPT) alanine transaminase (ALT) =< 3.0 x the
institutional ULN; if value is higher due to hepatic involvement by CLL, patient is
eligible

- Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial
thromboplastin time (PTT) activated partial thromboplastin time (aPTT) < 1.5 X ULN; if
value is higher due to hepatic involvement by CLL, patient is eligible

- No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic
treatment; patients who have a positive Coombs test but no evidence of hemolysis are
NOT excluded from participation

- No current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of
prednisone or equivalent dose of other steroid) used for treatment of non-hematologic
medical condition (e.g. chronic adrenal insufficiency) is permitted

- No previous use of corticosteroids for autoimmune complications that have developed
since the initial diagnosis of CLL; prior use of corticosteroids for reasons other
than treatment of autoimmune complications is allowed

- No other active primary malignancy (other than non-melanomatous skin cancer or
carcinoma in situ of the cervix) requiring treatment or limiting expected survival to
=< 2 years; NOTE: if there is a history of prior malignancy, they must not be
receiving other specific treatment (other than hormonal therapy for their cancer)

- Able to adhere to the study visit schedule and other protocol requirements

- No major surgery within the last 4 weeks (28 days) of first dose of study drug or
minor surgery within 3 days of first dose of study drug

- No radiation therapy =< 4 weeks prior to registration

- Patients with human immunodeficiency virus (HIV) infection may be eligible provided
they meet the following criteria:

- CD4-positive cell count >= lower limit of institutional normal

- HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL (if not on anti-HIV
therapy) OR < 50 copies HIV RNA/mL (if on anti-HIV therapy)

- No evidence of hepatitis B or C infection

- No evidence of resistant strains of HIV

- No history of acquired immune deficiency syndrome (AIDS)-defining condition

- Patients must not have any of the following conditions:

- Congestive heart failure or New York Heart Association Functional Classification
III or IV congestive heart failure

- History of myocardial infarction, unstable angina, or acute coronary syndrome
within 6 months prior to registration

- Recent infections requiring systemic treatment; need to have completed
anti-biotic therapy > 14 days before the first dose of study drug

- Cerebral vascular accident or intracranial bleed within the last 6 months

- Infection with known chronic, active hepatitis C

- Serologic status reflecting active hepatitis B or C infection; patients that are
positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior
to enrollment (PCR positive patients will be excluded)

- Patients are not eligible if they require treatment with a strong cytochrome P450
(CYP) family 3, subfamily A (3A) inhibitor

- Patients may not be on any other investigational agents

- Patients may not have received warfarin or another vitamin K antagonist in the
preceding 30 days

- Women must not be pregnant or breast-feeding; female patients of childbearing
potential must have a negative serum pregnancy test within 2 weeks prior to
registration to rule out pregnancy; female patients who are of non-reproductive
potential are those who are post-menopausal by history (i.e. no menses for >= 1 year);
OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of
bilateral oophorectomy

- Women of childbearing potential and sexually active males must be strongly advised to
use an accepted and effective method of contraception or to abstain from sexual
intercourse for 90 days after the last dose of study drug

- Patient must be able to swallow capsules and not have the following conditions:

- Disease significantly affecting gastrointestinal function

- Resection of the stomach or small bowel

- Symptomatic inflammatory bowel disease

- Ulcerative colitis

- Partial or complete bowel obstruction

- Patient must not be on any other systemic immunosuppressant therapy other than
corticosteroids within 28 days of the first dose of study drug

- Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first
dose of study drug

- Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or
hemophilia

- Patient must not have currently active, clinically significant hepatic impairment (>=
moderate hepatic impairment according to the NCI/Child Pugh)