Fludarabine and Cyclophosphamide With or Without Oblimersen in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

Sponsor

Genta Incorporated (Industry)

Overall Status

Completed

CT.gov ID

NCT00024440

Collaborator

(none)

Location

67.1

Duration (Months)

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Oblimersen may help fludarabine and cyclophosphamide kill more cancer cells by making them more sensitive to the drugs. It is not yet known if fludarabine and cyclophosphamide are more effective with or without oblimersen.

PURPOSE: Randomized phase III trial to compare the effectiveness of fludarabine and cyclophosphamide with or without oblimersen in treating patients who have relapsed or refractory chronic lymphocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: filgrastim Biological: oblimersen sodium Drug: cyclophosphamide Drug: fludarabine phosphate	Phase 3

Detailed Description

OBJECTIVES:

Compare the complete response and nodular partial response of patients with relapsed or refractory chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide with or without oblimersen.
Compare the overall response rate, response duration, survival, and time to progression in patients treated with these regimens.
Compare the clinical benefit and safety of these regimens in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to disease response to prior fludarabine-containing therapy (responsive vs refractory), number of prior regimens (1-2 vs 3 or more), and duration of response to last prior therapy (more than 6 months vs 6 months or fewer). Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive oblimersen IV continuously on days 1-7 via an infusion pump (ending on day 8) and fludarabine IV over 20-30 minutes and cyclophosphamide IV over 30-60 minutes on days 5-7. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 11 and continuing until blood counts recover.
Arm II: Patients receive fludarabine IV over 20-30 minutes followed by cyclophosphamide IV over 30-60 minutes on days 1-3. Patients also receive G-CSF SC beginning on day 7 and continuing until blood counts recover.

Treatment in both arms continues every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed at 1 month and then every 2 months for 2 years.

PROJECTED ACCRUAL: A total of 200 patients (100 per arm) will be accrued for this study within 1 year.

Study Design

Study Type:

Interventional

Allocation:

Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized Study Of Fludarabine And Cyclophosphamide With Or Without Genasense (Bcl-2 Antisense Oligonucleotide) In Subjects With Relapsed Or Refractory Chronic Lymphocytic Leukemia

Study Start Date :

Jul 1, 2001

Actual Study Completion Date :

Feb 1, 2007

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of relapsed or refractory chronic lymphocytic leukemia (CLL) requiring therapy
Primary resistance, defined as disease progression without response during at least 2 courses of myelosuppressive therapy OR
Relapsed disease, defined as a response (remission or plateau) followed by relapse on or off prior therapy
At least 1 prior regimen must have contained fludarabine
Intermediate or high-risk CLL
Intermediate-risk disease must satisfy at least 1 of the following criteria for active disease:
Massive or progressive splenomegaly and/or lymphadenopathy
Spleen tip greater than 6 cm below costal margin
More than 10% weight loss within the past 6 months
Grade 2 or 3 fatigue
Fevers greater than 100.5 degrees F or night sweats for more than 2 weeks without evidence of infection
Progressive lymphocytosis with an increase of more than 50% over a 2-month period or an anticipated doubling time of less than 6 months
Worsening anemia or thrombocytopenia
Measurable disease with all of the following:
Absolute lymphocytosis greater than 5,000/mm^3
Lymphocytosis of small to moderate-size lymphocytes with less than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically determined by manual differential
Bone marrow aspirate smear with at least 30% nucleated cells that are lymphoid or a bone marrow core biopsy showing lymphoid infiltrates compatible with CLL
Normocellular or hypercellular bone marrow
Lymphocyte immunophenotype that shows a predominant B-cell monoclonal population
No Rai stage 0 CLL or stable CLL not requiring therapy
No secondary leukemia or history of antecedent hematologic disorder prior to initial onset of CLL (e.g., myelodysplasia)

PATIENT CHARACTERISTICS:

Age:

Over 18

Performance status:

ECOG 0-2

Life expectancy:

Not specified

Hematopoietic:

See Disease Characteristics
Platelet count at least 50,000/mm^3 (hematopoietic growth factor or transfusion independent)
Negative Coombs' test
No bleeding or coagulation disorder
No history of hemolytic anemia, including autoimmune hemolytic anemia
No history of autoimmune thrombocytopenia

Hepatic:

Albumin at least 3.0 g/dL
Bilirubin no greater than 2 mg/dL
AST no greater than 1.5 times upper limit of normal (ULN) (5 times ULN if due to CLL)
PT no greater than 1.5 times ULN OR
INR no greater than 1.3
PTT no greater than 1.5 times ULN
No chronic hepatitis or cirrhosis

Renal:

Creatinine no greater than 2.0 mg/dL

Cardiovascular:

No uncontrolled congestive heart failure
No active symptoms of coronary artery disease (i.e., uncontrolled arrhythmia or recurrent chest pain despite prophylactic medication)
No New York Heart Association class III or IV disease
No cardiovascular signs or symptoms grade 2 or greater

Other:

Able to maintain an ambulatory infusion pump
HIV negative
No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
No known hypersensitivity to phosphorothioate-containing oligonucleotides, fludarabine, or cyclophosphamide
No concurrent medical disease that would preclude study participation
No uncontrolled seizure disorder
No unresolved serious infection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

No prior autologous or allogeneic stem cell transplantation
At least 3 weeks since prior immunologic therapy, cytokine therapy, vaccine therapy, or other biologic therapy for CLL and recovered
No concurrent interleukin-11