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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Terminated

CT.gov ID

NCT00612612

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: obatoclax mesylate Drug: fludarabine phosphate Biological: rituximab Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVE:

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:

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 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Study Start Date :

Jan 1, 2008

Actual Primary Completion Date :

Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (obatoclax mesylate, fludarabine, rituximab) 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.	Drug: obatoclax mesylate Given IV Other Names: GX15-070MS Drug: fludarabine phosphate Given IV Other Names: 2-F-ara-AMP Beneflur Fludara Biological: rituximab Given IV Other Names: IDEC-C2B8 IDEC-C2B8 monoclonal antibody Mabthera MOAB IDEC-C2B8 Rituxan Other: laboratory biomarker analysis Correlative study

Arm

Intervention/Treatment

Experimental: Treatment (obatoclax mesylate, fludarabine, rituximab)

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.

Drug: obatoclax mesylate

Given IV

Other Names:

GX15-070MS

Drug: fludarabine phosphate

Given IV

Other Names:

2-F-ara-AMP

Beneflur

Fludara

Biological: rituximab

Given IV

Other Names:

IDEC-C2B8

IDEC-C2B8 monoclonal antibody

Mabthera

MOAB IDEC-C2B8

Rituxan

Other: laboratory biomarker analysis

Correlative study

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of obatoclax mesylate [28 days]
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.

Secondary Outcome Measures

Response evaluated using the Revised National Cancer Institute-sponsored Working Group Guidelines [Up to 2 years]
Described using descriptive statistics. Ninety-five percent confidence intervals will be calculated where appropriate.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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