FCR or BR in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fludarabine, cyclophosphamide, and bendamustine, 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. It is not yet known whether giving fludarabine and cyclophosphamide together with rituximab is more effective than giving bendamustine together with rituximab in treating chronic lymphocytic leukemia. PURPOSE: This randomized phase III trial is studying fludarabine, cyclophosphamide, and rituximab to see how well they work compared with bendamustine and rituximab in treating patients with previously untreated B-cell chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: To compare the therapeutic efficacy of fludarabine phosphate, cyclophosphamide, and rituximab vs bendamustine hydrochloride and rituximab in patients with previously untreated B-cell chronic lymphocytic leukemia. To compare the incidence of major side effects (e.g., myelosuppression) associated with these regimens in these patients. To compare the rate of infections and secondary neoplasias in patients treated with these regimens. OUTLINE: This is a multicenter study. Patients are stratified according to country and disease stage. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive fludarabine phosphate IV and cyclophosphamide IV on days 1-3. Patients also receive rituximab IV on day 0 of course 1 and on day 1 of courses 2-6. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive bendamustine hydrochloride IV on days 1 and 2. Patients also receive rituximab as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients complete quality of life questionnaires (EORTC-C30 and EURO-QOL) at baseline and then at 12, 24, 36, 48, and 60 months. After completion of study therapy, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then once a year thereafter.

Official Title
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Phase III Trial of Combined Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab (FCR) Versus Bendamustine and Rituximab (BR) in Patients With Previously Untreated Chronic Lymphocytic Leukaemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Biological: Rituximab
* Drug: Bendamustine
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Confirmed diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting 1 of the following criteria: Binet stage C disease or stage B or A disease requiring treatment Binet stage B or A disease meeting ≥ 1 of the following: B-symptoms (e.g., night sweats, weight loss ≥ 10% within the past 6 months, fevers > 38°C or 100.4°F for ≥ 2 weeks without evidence of infection) or constitutional symptoms (e.g., fatigue) Progressive lymphocytosis, defined as peripheral lymphocyte count > 5 x 10^9/L (i.e., > 50% increase over a 2-month period or doubling of peripheral blood lymphocyte count < 6 months) Evidence of progressive marrow failure as manifested by the development/worsening of anemia and/or thrombocytopenia Massive, progressive, or painful splenomegaly or hypersplenism Massive lymph nodes or lymph node clusters (> 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy No 17p deletion by FISH No aggressive B-cell cancer, such as Richter syndrome PATIENT CHARACTERISTICS: WHO performance status 0-2 Life expectancy ≥ 6 months Total bilirubin ≤ 2 times upper limit of normal (ULN) (unless directly attributable to CLL) AST and ALT ≤ 2 times ULN (unless directly attributable to CLL) Creatinine clearance ≥ 70 mL/min (creatinine clearance is to be calculated only in patients with serum creatinine ≥ 1.1 mg/dL) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy Hepatitis B and C negative HIV negative CIRS score > 6 or a single score of 4 for one organ category No active secondary malignancy requiring treatment, except basal cell carcinoma or malignant tumor curatively treated by surgery, or successfully treated secondary malignancies in complete remission > 5 years prior to enrollment No history of anaphylaxis following exposure to monoclonal antibodies No active bacterial, viral, or fungal infection No medical condition requiring prolonged use of oral corticosteroids (i.e., > 1 month) No cerebral dysfunction or legal incapacity No circumstance that would preclude completion of the study or the required follow-up PRIOR CONCURRENT THERAPY: No prior CLL specific-chemotherapy, radiotherapy, and/or immunotherapy Prednisolone administered immediately prior to initiation of study therapy allowed for very high lymphocyte counts No concurrent participation in another clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FCR<br> | Biological: Rituximab<br>* cycle 1: 375 mg/m² i.v., day 0, q28d cycle 2-6: 500 mg/m² i.v., day 1, q28d<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* cycle 1-6: 250 mg/m² i.v., days 1-3, q28d<br>* Other names: Endoxan;Drug: Fludarabine<br>* cycle 1-6: 25 mg/m² i.v., days 1-3, q28d<br>* Other names: Fludura;|
| Experimental: BR<br> | Biological: Rituximab<br>* cycle 1: 375 mg/m² i.v., day 0, q28d cycle 2-6: 500 mg/m² i.v., day 1, q28d<br>* Other names: Rituxan;Drug: Bendamustine<br>* cycle 1-6: 90mg/m² i.v., day 1-2, q28d<br>* Other names: Treanda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival rate after 24 months | estimated time point when 198 needed events for the final analysis(PD or deaths) have occured. | 2008-2015 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal residual disease, complete response rates, and partial response rates | done within the final analysis | 2008-2015 | 
| Duration of remission | done within the final analysis | 2008-2015 | 
| Event-free survival | done within the final analysis | 2008-2015 | 
| Overall survival | done within the final analysis | 2008-2015 | 
| Overall response rate | done within the final analysis | 2008-2015 | 
| Response rates in and survival times in biological subgroups | done within the final analysis | 2008-2015 | 
| Toxicity rates | done within the final analysis | 2008-2015 | 
| Quality of life | done within the final analysis | 2008-2015 | 
| Standard safety analysis | done within the final analysis | 2008-2015 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-cell chronic lymphocytic leukemia, stage 0 chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia