Obatoclax, Fludarabine, and Rituximab in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia

OBJECTIVES:

Primary

- To determine the maximum-tolerated dose of obatoclax mesylate in combination with
fludarabine phosphate-rituximab (FR)-based chemoimmunotherapy in patients with relapsed
chronic lymphocytic leukemia.

Secondary

- To evaluate toxicity of obatoclax mesylate in combination with FR in this patient
population.

- To determine objective response rate and progression-free survival of obatoclax
mesylate in combination with FR.

- To correlate levels of anti-apoptotic Bcl-2 family members with drug response.

- To determine whether apoptosis is induced via the mitochondrial pathway in response to
obatoclax mesylate and further enhanced by FR.

OUTLINE: This is a dose-escalation study of obatoclax mesylate.

Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 15
minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only).
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

Patients enrolled in dose level 5 receive obatoclax mesylate IV over 3 hours, fludarabine IV
over 15 minutes and cyclophosphamide IV over 60-90 minutes on days 1-3, and rituximab as
above. Treatment repeats every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity.

Patients undergo peripheral blood collection for correlative studies. Samples are analyzed
for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis
induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP
cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR
amplification and direct sequencing.

After completion of study therapy, patients are followed every 3 months.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed diagnosis of B-cell chronic lymphocytic
leukemia (B-CLL) or prolymphocytic leukemia (PLL) arising from CLL

- No de novo PLL

- Malignant B cells must co-express CD5 with CD19 or CD20

- Patients who lack CD23 expression on their leukemia cells may not have t(11;14)
or cyclin D1 overexpression, to rule out mantle cell lymphoma

- Must have documented lymphocytosis of > 5,000/μL

- Must require therapy based on any of the following criteria:

- Massive or progressive splenomegaly and/or lymphadenopathy

- Anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100,000/µL)

- Presence of weight loss > 10% over the preceding 6-month period

- NCI grade 2 or 3 fatigue

- Fevers > 100.5 F or night sweats for > 2 weeks without evidence of infection

- Progressive lymphocytosis with an increase of > 50% over a 2-month period or an
anticipated doubling time of less than 6 months

- Must have received at least one prior therapy for B-CLL

- No known brain metastases

PATIENT CHARACTERISTICS:

Inclusion criteria:

- See Disease Characteristics

- ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%

- Life expectancy > 3 months

- Total bilirubin normal (unless due to Gilbert syndrome or compensated hemolysis)

- AST and ALT < 2.5 times upper limit of normal

- Creatinine normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

Exclusion criteria:

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to obatoclax mesylate or other agents used in study

- Active Coombs' positive autoimmune hemolytic anemia

- Chronic active hepatitis B patients if not on appropriate antiviral therapy (e.g.,
lamivudine, adefovir)

- Uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia including QTc > 450 msec

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Other neurological disorders or dysfunction or a history of seizure disorder

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from all prior therapy

- Any number of prior therapies allowed

- At least 1 year since prior fludarabine phosphate-rituximab combination therapy

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No chemotherapy or radiotherapy within the past 4 weeks (6 weeks for nitrosoureas or
mitomycin C)

- No other concurrent investigational agents