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

Phase 3
18 Years
Open (Enrolling)

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Trial Information

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


- 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.

Inclusion Criteria


- Diagnosis of relapsed or refractory chronic lymphocytic leukemia (CLL) requiring

- 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)



- Over 18

Performance status:

- ECOG 0-2

Life expectancy:

- Not specified


- See Disease Characteristics

- Platelet count at least 50,000/mm^3 (hematopoietic growth factor or transfusion

- Negative Coombs' test

- No bleeding or coagulation disorder

- No history of hemolytic anemia, including autoimmune hemolytic anemia

- No history of autoimmune thrombocytopenia


- 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


- Creatinine no greater than 2.0 mg/dL


- 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


- 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


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


- See Disease Characteristics

- At least 3 weeks since prior chemotherapy and recovered

Endocrine therapy:

- No concurrent corticosteroid therapy


- At least 3 weeks since prior radiotherapy for CLL and recovered


- No prior organ allograft

- At least 3 weeks since prior major surgery for CLL and recovered


- At least 3 weeks since other prior therapy for CLL and recovered

- No other concurrent investigational therapy

- No concurrent therapeutic anticoagulation

- No concurrent immunosuppressive drugs

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Stanley R. Frankel, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Genta Incorporated


United States: Federal Government

Study ID:




Start Date:

July 2001

Completion Date:

Related Keywords:

  • Leukemia
  • refractory chronic lymphocytic leukemia
  • B-cell chronic lymphocytic leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid



Genta Incorporated Berkeley Heights, New Jersey  07922