Fludarabine, Cyclophosphamide, and Rituximab or Alemtuzumab in Treating CLL2007 CLL 2007 FMP

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to kill cancer cells or stop them from growing. Monoclonal antibodies, such as rituximab and alemtuzumab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. It is not yet known whether giving fludarabine and cyclophosphamide together with rituximab is more effective than giving fludarabine and cyclophosphamide together with alemtuzumab in treating B-cell chronic lymphocytic leukemia. PURPOSE: This randomized phase III trial is studying giving fludarabine together with cyclophosphamide and rituximab to see how well it works as first-line therapy compared with giving fludarabine together with cyclophosphamide and alemtuzumab in treating patients with B-cell chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary To compare 36-month progression-free survival in patients with Binet stage B or C B-cell chronic lymphocytic leukemia treated with first-line therapy comprising fludarabine phosphate and cyclophosphamide and either rituximab or alemtuzumab. Secondary To compare the disease-free survival, event-free survival, and overall survival of patients treated with these regimens. To compare time to next treatment in patients treated with these regimens. To compare the overall response rate (complete response [CR] and partial response [PR]) in patients treated with these regimens. To compare the rate of phenotypic and molecular response in patients treated with these regimens. To compare the duration of phenotypic, molecular, complete and partial responses in patients treated with these regimens. To compare the response rates and survival times in biological subgroups. To compare the rates of treatment-related adverse effects in patients treated with these regimens. To compare the quality of life of patients treated with these regimens. Minimal residual disease study. OUTLINE: This is a multicenter study. Patients are stratified according to Ig mutational status and cytogenetic abnormalities. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive rituximab IV on day 1 and fludarabine phosphate and cyclophosphamide IV or orally on days 2-4 of course 1. Beginning in course 2 and for all subsequent courses, patients receive rituximab IV on day 1 and fludarabine phosphate and cyclophosphamide IV or orally on days 1-3. Arm II: Patients receive alemtuzumab subcutaneously, oral fludarabine phosphate, and oral cyclophosphamide on days 1-3. In both arms, treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months.

Official Title
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Randomized Phase-III Trial Comparing Fludarabine and Cyclophosphamide Plus Rituximab (FCR) to FC and MabCampath (FCCam) for Previously Untreated Fit Patients With Chronic Lymphocytic Leukemia (CLL)

Conditions
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Leukemia

Intervention / Treatment
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* Biological: Campath
* Biological: rituximab
* Drug: cyclophosphamide
* Drug: fludarabine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Inclusion Diagnosis of B-cell chronic lymphocytic leukemia (CLL), meeting the following criteria: Binet classification stages B or C Del 17 p (FISH) negative (< 10 % positives cores) Matutes score 4 or 5 Exclusion Transformation to aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia) PATIENT CHARACTERISTICS: Exclusion ECOG performance status ≥ 2 Life expectancy < 6 months Creatinine clearance < 60 mL/min Total bilirubin > 2 x upper limit of normal (ULN) Gamma glutamyltransferase or transaminase levels > 2 x ULN Cumulative illness rating scale > 6 HIV seropositivity Hepatitis B or C seropositivity (unless clearly due to vaccination) Clinically significant autoimmune anemia Active bacterial, viral, or fungal infection Active second malignancy currently requiring treatment (except basal cell carcinoma or in situ endometrial carcinoma) and/or less than 5 years complete remission after breast cancer Any severe comorbid conditions including, but not limited to, any of the following: Class III or IV heart failure Recent myocardial infarction Unstable angina Ventricular tachyarrhythmias requiring ongoing treatment Severe chronic obstructive pulmonary disease with hypoxemia Uncontrolled diabetes mellitus Uncontrolled hypertension Concomitant disease requiring prolonged use of corticosteroids (> 1 month) Known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs Contraindication to the use of rituximab or alemtuzumab according to Summary of Product Characteristics Any coexisting medical or psychological condition that would preclude participation in the required study procedures Any mental deficiency preventing proper understanding of the requirements of treatment Person under law control Pregnant or breastfeeding women Fertile patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study PRIOR CONCURRENT THERAPY: Inclusion No prior chemotherapy, radiotherapy, or immunotherapy for CLL Corticosteroids within the past month allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: FCCAM<br>Fludarabine-Cyclophosphamide-Campath (FCCam) Oral Fludarabine: 40 mg/m2 per os, D1 to D3 Oral Cyclophosphamide: 250 mg/m2/day as one dose at noon, D1 to D3 Campath®: 30 mg sc, D1 to D3 without dose escalation | Biological: rituximab<br>* Fludarabine-Cyclophosphamide-Rituximab (FCR)<br>* Other names: Mabthera®;Drug: cyclophosphamide<br>* Fludarabine-Cyclophosphamide-Campath (FCCAM) Fludarabine-Cyclophosphamide-Rituximab (FCR)<br>* Other names: Endoxan®;Drug: fludarabine<br>* Fludarabine-Cyclophosphamide-Campath (FCCAM) Fludarabine-Cyclophosphamide-Rituximab (FCR)<br>* Other names: Fludara®;|
| Active Comparator: FCR<br>Fludarabine-Cyclophosphamide-Rituximab (FCR) First course: Rituximab 375 mg/m2 on D1. D2 to D4: oral Fludarabine: 40 mg/m2/day as a single morning dose oral Cyclophosphamide: 250 mg/m2/day as a single dose at noon Subsequent courses (2 to 6) Rituximab 500 mg/m2 on D1 D1 to D3: oral Fludarabine: 40 mg/m2/day as a single morning dose oral Cyclophosphamide: 250 mg/m2/day as a single dose at noon | Biological: Campath<br>* Fludarabine-Cyclophosphamide-Campath (FCCam)<br>* Other names: Alemtuzumab;Drug: cyclophosphamide<br>* Fludarabine-Cyclophosphamide-Campath (FCCAM) Fludarabine-Cyclophosphamide-Rituximab (FCR)<br>* Other names: Endoxan®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival at 36 months |  | 36 months follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival |  | 36 months follow up | 
| Event-free survival |  | 36 months follow up | 
| Overall survival |  | 36 months follow up | 
| Time to next treatment |  | 36 months follow up | 
| Overall response rate (complete response [CR] and partial response [PR]) |  | 36 months follow up | 
| Duration of phenotypic, molecular, NCI complete and partial responses |  | 36 months follow up | 
| Response rates and survival times in biological subgroups |  | 36 months follow up | 
| Treatment-related adverse effects |  | 36 months follow up | 

 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 I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia