Rituximab, Fludarabine, and Cyclophosphamide or Observation Alone in Treating Patients With Stage 0, Stage I, or Stage II Chronic Lymphocytic Leukemia

German CLL Study Group

Status and phase: Completed; Phase 3

Conditions: Chronic Lymphocytic Leukemia

Treatments: Drug: Fludarabine; Biological: Rituximab; Drug: Cyclophosphamide

Study type: Interventional

Funder types: Other

Identifiers

NCT00275054

EU-20559

ROCHE-GCLLSG-CLL7

CLL7

2005-003018-14 (EudraCT Number)

Details and patient eligibility

About

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether giving rituximab together with fludarabine and cyclophosphamide is more effective than observation alone in treating chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying rituximab, fludarabine, and cyclophosphamide to see how well they work compared to observation alone in treating patients with stage 0, stage I, or stage II B-cell chronic lymphocytic leukemia.

Full description

OBJECTIVES:

Primary

• Compare the effect, in terms of event-free survival, of deferred versus immediate treatment with rituximab, fludarabine, and cyclophosphamide in patients with previously untreated Binet stage A chronic lymphocytic leukemia at high risk for disease progression.
• Investigate and define a new prognostic staging system for patients with Binet stage A chronic lymphocytic leukemia.

Secondary

• Compare the time to progression to Binet stages B and C in patients treated with these regimens.
• Compare the overall and progression-free survival of patients treated with these regimens.
• Compare the quality of life of patients treated with these regimens.
• Compare the time to treatment in patients treated with these regimens.
• Analyze the pharmacoeconomics of these regimens in these patients.
• Determine the overall response rate (partial and complete) in patients included in the early treatment arm.
• For patients included in the early treatment arm in complete remission, determine the percentage achieving complete molecular remission using the clone-specific CDR-III region as follow-up parameter.
• Determine the duration of response in patients included in the early treatment arm.
• Determine any adverse events related to treatment/safety of treatment.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to risk factor profile (< 2 risk factors [low risk] vs ≥ 2 risk factors [high risk]). Low-risk patients are assigned to arm II. High-risk patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive rituximab IV on day 1, fludarabine IV on days 1-3, and cyclophosphamide IV on days 1-3. Treatment repeats every 28 days for up to 6 courses.
• Arm II: Patients undergo observation only until disease progression.

PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study.

Enrollment: 825 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Established diagnosis of B-cell chronic lymphocytic leukemia

  • First diagnosis within 12 months before inclusion in study
  • Previously untreated disease

• Binet stage A disease (Rai stage 0, I, or II)

PATIENT CHARACTERISTICS:

• Life expectancy > 6 months
• ECOG performance status 0-2
• Willingness to accept contraception (if randomized to arm I) for the duration of therapy and 12 months thereafter
• Negative serum pregnancy test
• All parameters for risk stratification (lymphocyte doubling time, cytogenetics, unmutated IgVH, and serum thymidine kinase level > 10) present

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, radiotherapy, or antibody treatment
• No other concurrent chemotherapy

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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825 participants in 3 patient groups

Cohort I (FCR)

Experimental group

Description:

Patients with 2 or more risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) who are randomized into cohort I receive Fludarabine, Cyclophosphamide and Rituximab (FCR) chemoimmunotherapy.

Treatment:

Drug: Cyclophosphamide

Biological: Rituximab

Drug: Fludarabine

Cohort II (W&W)

No Intervention group

Description:

Patients with 2 or more risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) who are randomized into cohort II receive no treatment at all (watch \& wait).

Cohort III (W&W)

No Intervention group

Description:

Patients with less than 2 risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) are assigned directly to cohort III and receive no treatment at all (watch \& wait).