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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)

Phase 1
18 Years
Open (Enrolling)
B-cell Chronic Lymphocytic Leukemia, Leukemia, Prolymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia

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Trial Information

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.

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:

- Massive or progressive splenomegaly and/or lymphadenopathy

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

- 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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of obatoclax mesylate

Outcome Description:

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.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Jennifer Brown

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

January 2008

Completion Date:

Related Keywords:

  • B-cell Chronic Lymphocytic Leukemia
  • Leukemia
  • Prolymphocytic Leukemia
  • Refractory Chronic Lymphocytic Leukemia
  • Stage I Chronic Lymphocytic Leukemia
  • Stage II Chronic Lymphocytic Leukemia
  • Stage III Chronic Lymphocytic Leukemia
  • Stage IV Chronic Lymphocytic Leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Leukemia, Prolymphocytic



Dana-Farber Cancer Institute Boston, Massachusetts  02115