A Phase 1 Study of Obatoclax Mesylate (GX15-070MS) in Combination With Fludarabine-Based Chemoimmunotherapy in Previously Treated Patients With B-Cell Chronic Lymphocytic Leukemia (B-CLL)
A Phase 1 Study of Obatoclax Mesylate (GX15-070MS) in Combination With Fludarabine-Based Chemoimmunotherapy in Previously Treated Patients With B-Cell Chronic Lymphocytic Leukemia (B-CLL)
Obatoclax may stop the growth of chronic lymphocytic leukemia by blocking blood flow to the cancer and by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving obatoclax together with fludarabine and rituximab may kill more cancer cells. This phase I trial is studying the side effects and best dose of obatoclax when given together with fludarabine and rituximab in treating patients with B-cell chronic lymphocytic leukemia.
PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose of obatoclax mesylate in combination with fludarabine phosphate-rituximab (FR) in patients with relapsed chronic lymphocytic leukemia.
SECONDARY OBJECTIVES:
I. To evaluate toxicity of obatoclax mesylate in combination with FR in this patient population.
II. To determine objective response rate and progression-free survival of obatoclax mesylate in combination with FR.
III. To correlate levels of anti-apoptotic Bcl-2 family members with drug response.
IV. 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 20-30 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 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 6 months.
Inclusion Criteria:
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/uL
Must require therapy based on any of the following criteria:
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
ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%
Total bilirubin normal (unless due to Gilbert syndrome or compensated hemolysis)
Life expectancy > 3 months
Creatinine normal
Fertile patients must use effective contraception
Not pregnant or nursing
Negative pregnancy test
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
AST and ALT < 2.5 times upper limit of normal
Recovered from all prior therapy
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)
Other neurological disorders or dysfunction or a history of seizure disorder
Uncontrolled intercurrent illness including, but not limited to, any of the following: