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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
N/A
Open (Enrolling)
Both
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)


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:

- 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
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

Type of Study:

Interventional

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:

Yes

Principal Investigator

Jennifer Brown

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00254

NCT ID:

NCT00612612

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

Name

Location

Dana-Farber Cancer InstituteBoston, Massachusetts  02115