Ibrutinib in Treating Minimal Residual Disease in Patients With Chronic Lymphocytic Leukemia After Front-Line Therapy

PRIMARY OBJECTIVES:

I. Determine the rate of minimal residual disease (MRD)-negative responses (in both blood and
bone marrow) at any time during treatment with ibrutinib maintenance.

SECONDARY OBJECTIVES:

I. Median time to achieve MRD- (negative) status (in blood and in bone marrow) after
initiation of ibrutinib maintenance treatment.

II. Toxicity profile of ibrutinib as maintenance therapy after frontline induction.

III. Durability of the MRD- state (determined from the time of first documentation of MRD-
until the first documentation of MRD+ (positive) (or last date shown to be MRD- for a
censor).

IV. Determine the number of patients who improve their remission category (i.e., upgrade
clinical response achieved after the induction such as from partial response [PR] to complete
response [CR]) after initiating the maintenance therapy.

V. Time to requirement of next therapy for patients who achieve confirmed MRD- vs. those who
remain MRD+ disease at 48 weeks (end of 12 cycles).

VI. Progression free survival (as determined by the International Workshop on Chronic
Lymphocytic Leukemia [IWCLL] criteria) among patients who achieve confirmed MRD- vs. those
who remain MRD+ disease at 48 weeks (end of 12 cycles).

TERTIARY OBJECTIVES:

I. To conduct correlative studies for further understanding of the mechanism of antitumor
activity of ibrutinib in eradication of the MRD.

II. Determine the impact of ibrutinib on depression and anxiety symptoms to better understand
toxicity profile of ibrutinib maintenance.

III. Determine impact of social support or lack thereof on mood symptoms in chronic
lymphocytic leukemia (CLL) patients receiving maintenance treatment.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Treatment repeats every
4 weeks* for up to 36 courses in the absence of disease progression or unacceptable toxicity.

Note: *The last course may last up to 56 days to accommodate the study drug discontinuation
visit.

After completion of study treatment, patients are followed up every 3-6 months for up to 2
years.

Inclusion Criteria:

- Understand and voluntarily sign an informed consent form

- Able to adhere to the study visit schedule and other protocol requirements including
willing to provide blood, baseline bone marrow aspirate, and control deoxyribonucleic
acid (DNA) samples for correlative research purposes

- Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL), confirmed by flow cytometry
and as per the criteria outlined by the IWCLL/Hallek December 2008

- Prior frontline therapy for B-CLL must have been discontinued >= 56 days but =< 365
days prior to registration; NOTE: Patients on supportive care therapy due to use of
specific induction regimen such as antibiotics may continue on those treatments at the
discretion of the treating physician

- Patient must have completed a frontline induction therapy (minimum of 2 treatment
cycles); NOTE: Standard therapies/therapeutic agents are defined as those listed in
the National Comprehensive Cancer Network (NCCN) guidelines for treatment of CLL;
also, patients who received induction regimen as part of a clinical trial and is not
necessarily mentioned in the NCCN guidelines, will also be eligible as long as the
patient has completed at least 2 treatment cycles of induction regimen, achieved a
clinical response (PR or CR) and is able to meet all other criteria for the study;
however, patients who have previously received ibrutinib or have been randomized to
ibrutinib containing arms in a clinical trial will not be eligible for this study

- Patients must have a sustained clinical response (PR, nodular PR [nPR], complete
clinical response [CCR], CR with incomplete marrow recovery [CRi], CR) with documented
residual disease (>= 1 CLL cell per 10,000 leukocytes or >= 0.01% MRD) either in the
blood, bone marrow or a lymph node >= 3.5 cm by any available techniques

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 at
registration

- Absolute neutrophil count >= 1000/mm^3

- Platelet count >= 30,000/mm^3

- Serum creatinine =< 1.5 x upper limit of normal (ULN)

- Total bilirubin =< 1.5 mg/dL or direct bilirubin =< 1.0 mg/dL for patients with
Gilbert's syndrome

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.5 x
ULN

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

Exclusion Criteria:

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form

- Since this study involves an investigational agent whose genotoxic, mutagenic and
teratogenic effects on the developing fetus and newborn are unknown, any of the
following will deem the subject ineligible for the study:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study

- Use of any other experimental drug or therapy =< 28 days prior to registration on this
study; NOTE: Patients on low dose prednisone (=< 10 mg) for treatment of conditions
other than CLL are eligible

- Patients who have received more than 1 prior therapy; NOTE: Prior therapy is defined
as any single agent or combination regimen that is included as treatment for
symptomatic CLL; treatment(s) given prior to the symptomatic phase of the disease
(preventive strategy) will not be considered as prior induction therapy; for the
purpose of a particular therapy/regimen to be counted towards the number of prior
treatments a patient must have received at least 2 cycles of the induction regimen
e.g., a patient who change their treatment regimen after only 1 cycle (due to toxicity
or any other reason) will not be considered to have "2" prior therapies

- Patients who have progressive disease or relapse (as defined by the IWCLL criteria) at
or any time before registration on this study

- Patients with history of any other cancer (except non-melanoma skin cancer or
carcinoma in-situ of the cervix, unless in complete remission and off therapy for that
disease for > 3 years)

- Patients who are already MRD- (both in the blood and the bone marrow) after frontline
therapy and have lymph nodes < 3.5 cm

- Concomitant use of warfarin or other vitamin K antagonists

- Requires treatment with a strong cytochrome P450 modulators (cytochrome P450, family
3, subfamily A [CYP3A] inhibitor and/or CYP3A inducers)

- Currently active, clinically significant hepatic impairment Child-Pugh class B or C
according to the Child Pugh classification

- Major surgery =< 4 weeks prior to registration

- Patients who have active infectious hepatitis

- Patients with other diseases that in the opinion of the treating physician pose a
higher risk for treatment with ibrutinib therapy including active human
immunodeficiency virus (HIV) infection and bleeding disorders