Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

PRIMARY OBJECTIVES:

I. To determine whether progression free survival (PFS) is superior after therapy with
bendamustine (bendamustine hydrochloride) in combination with rituximab, ibrutinib alone, or
ibrutinib in combination with rituximab in patients age 65 or older with previously untreated
chronic lymphocytic leukemia (CLL).

SECONDARY OBJECTIVES:

I. To determine 2-year PFS in each of the three treatment arms. II. To determine which
treatment arm produces superior overall survival (OS). III. To determine the complete
response (CR) rate, complete and nodular partial response (CR/nPR) rate, and overall response
(PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms.

IV. To determine the impact of minimal residual disease (MRD)-negative disease at time of CR
documentation and at 2 years on PFS and OS in each of the treatment arms.

V. To determine duration of response after each of the three treatments and compare these
treatment arms.

VI. To determine toxicity and tolerability of the three treatment regimens. VII. To determine
response and PFS of patients initially on the bendamustine in combination with rituximab arm
who cross over to ibrutinib.

VIII. To determine whether baseline cytogenetic markers, zeta-chain (TCR) associated protein
kinase 70kDa (Zap-70) methylation, immunoglobulin variable region (IgVH) mutational status,
or select deoxyribonucleic acid (DNA) mutations predict outcomes or time to response in these
three arms.

IX. To determine whether local fluorescent in situ hybridization (FISH) results for
del(11q22.3) and del(17p13.1) are consistent with central analysis.

X. To determine whether baseline micro ribonucleic acid (RNA) and gene expression markers are
correlated with clinical outcomes of interest (e.g. progression-free and alive at 2 years
versus not), as well as to explore changes in microRNA expression from baseline to
post-treatment time points, with a focus on those with persistent lymphocytosis and relapse.

XI. To determine whether eradication of MRD predicts longer duration of response with
standard therapy and ibrutinib-based regimens.

XII. To describe the baseline functional status, comorbid medical conditions, and number of
medications of older CLL patients who meet criteria for therapy.

XIII. To determine how functional status changes with therapy using baseline to 3-month
evaluation and end-of-study/2-year evaluation; to determine whether this change is different
among the treatment groups.

XIV. To determine whether geriatric assessment variables known to be associated with
chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity in
the CLL population.

XV. To assess whether the Fc fragment of IgG, low affinity IIIa, receptor (CD16a) (FCGR3A)
polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus
rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and
progression-free survival (PFS).

XVI. To assess whether complement component 1, q subcomponent, A chain (C1QA) polymorphism
(rs172378) is correlated with MRD status, CR rate, rapidity of response, and PFS.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive rituximab intravenously (IV) on day 1 (day 0 course 1) and
bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days
for 6 courses in the absence of disease progression or unacceptable toxicity. Patients
experiencing disease progression may crossover to Arm II.

ARM II: Patients receive ibrutinib orally (PO) daily on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8,
15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 10
years.

Inclusion Criteria:

- Patients must be diagnosed with CLL in accordance with International Workshop on
Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that includes all of the following:

- >= 5 x 10^9 B lymphocytes (5000/uL) in the peripheral blood

- On morphologic review, the leukemic cells must be small mature lymphocytes, and
prolymphocytes must not exceed 55% of the blood lymphocytes

- CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell
population, which express the B cell surface markers of cluster of
differentiation (CD)19 and CD20, as well as the T-cell antigen CD5; patients with
bright surface immunoglobulin expression or lack of CD23 expression in > 10% of
cells must lack t(11;14) translocation by interphase cytogenetics

- Patients must be intermediate or high-risk Rai stage CLL

- Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus
enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly

- High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without
enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or
thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to
autoimmune hemolytic anemia or thrombocytopenia

- Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines which
includes at least one of the following criteria:

- Evidence of marrow failure as manifested by the development or worsening of
anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or
thrombocytopenia)

- Massive (>= 6 cm below the costal margin), progressive or symptomatic
splenomegaly

- Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy

- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
therapy

- Constitutional symptoms, which include any of the following:

- Unintentional weight loss of 10% or more within 6 months

- Significant fatigue

- Fevers > 100.5 degrees F for 2 weeks or more without evidence of infection

- Night sweats > 1 month without evidence of infection

- Prior treatment

- Patients must not have had prior therapy for CLL (except palliative steroids or
treatment of autoimmune complications of CLL with rituximab or steroids)

- Treatment with rituximab and/or high dose corticosteroids for autoimmune
complications of CLL must be complete at least 4 weeks prior to enrollment;
palliative steroids must be at a dose not higher than 20 mg/day of prednisone or
equivalent corticosteroid at the time of registration

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Patients with active hepatitis B defined by hepatitis B surface antigen positivity or
core antibody positivity in the presence of hepatitis B DNA are not eligible for this
study; patients with a positive hepatitis B core antibody but with negative hepatitis
B DNA may participate, but must have hepatitis serologies and hepatitis B DNA
monitored periodically by the treating physician

- Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B
serology; if patients receiving routine IVIG have core antibody or surface
antigen positivity without evidence of active viremia (negative hepatitis B DNA)
they may still participate in the study, but should have hepatitis serologies and
hepatitis B DNA monitored periodically by the treating physician

- Patients must not be receiving active systemic anticoagulation with heparin or
warfarin; patients must be off warfarin therapy for at least 30 days prior to
enrollment

- Patients with class III or class IV heart failure by New York Heart Association, those
with unstable angina, and those with uncontrolled arrhythmia are not eligible

- Patients who have had a myocardial infarction, intracranial bleed, or stroke within
the past 6 months are not eligible

- Patients with human immunodeficiency virus (HIV) are eligible if their CD4 count is >=
350 cells/mm^3 and if they are not taking prohibited cytochrome (CYP)-interacting
medications

- Patients must not have any history of Richter's transformation or prolymphocytic
leukemia (prolymphocytes in blood > 55%)

- Patients must not require more than 20 mg prednisone or equivalent corticosteroid
daily

- Patients must not have uncontrolled active systemic infection requiring intravenous
antibiotics

- Patients must not have continued requirement for therapy with a strong cytochrome P450
3A4/5 (CYP3A4/5) inhibitor or inducer

- Patients must not have a known allergy to mannitol

- Patients must not have prior significant hypersensitivity to rituximab (not including
infusion reactions)

- Patients may not have had major surgery within 10 days of enrollment, or minor surgery
within 7 days of enrollment; examples of minor surgery include dental surgery,
insertion of a venous access device, skin biopsy, or aspiration of a joint; the
decision about whether a surgery is major or minor can be made at the discretion of
the treating physician

- Absolute neutrophil count (ANC) >= 1,000/uL unless due to bone marrow involvement

- Aspartate aminotransferase (AST) or alanine aminotransferase (AST) =< 2.5 x upper
limits of normal except if due to disease infiltration of the liver

- Bilirubin =< 1.5 x upper limits of normal (unless due to liver involvement, hemolysis,
or Gilbert's disease)

- Creatinine clearance >= 40 mL/min

- To be calculated by modified Cockcroft-Gault formula

- Platelet count (untransfused) >= 30,000/uL