Phase I Study of Obatoclax Mesylate (GX15-070MS) in Combination With Fludarabine and Rituximab in Previously Treated Patients With B-cell Chronic Lymphocytic Leukemia (B-CLL)
I. To determine the maximum tolerated dose of obatoclax mesylate in combination with
fludarabine phosphate-rituximab (FR) in patients with relapsed chronic lymphocytic leukemia.
I. To evaluate toxicity of obatoclax mesylate in combination with FR in this patient
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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of obatoclax mesylate
DLT will be defined as any non-hematologic toxicity of grade 3 or greater severity (excluding asymptomatic grade 3 laboratory abnormalities that are not life-threatening and respond to treatment; grade 3 fatigue; grade 3 nausea, vomiting or diarrhea occurring without optimal prophylaxis; or expected grade 3 rituximab infusion reactions). Any grade 4 non-hematological toxicity, as well as any irreversible grade 2 cardiac, renal or neurologic toxicities, will be considered dose-limiting. Grading of non-hematologic toxicities will be according to NCI CTC version 3.0.
Dana-Farber Cancer Institute
United States: Food and Drug Administration
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