Clinical trial NCT00769522: FCR or BR in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Keywords: 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
Lead sponsor: German CLL Study Group
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
name: Mundipharma Pte Ltd.
First posted: 2008-10-09
Enrollment: 564
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression-free survival rate after 24 months
timeFrame: 2008-2015
Secondary outcomes:
measure: Minimal residual disease, complete response rates, and partial response rates
timeFrame: 2008-2015
measure: Duration of remission
timeFrame: 2008-2015
measure: Event-free survival
timeFrame: 2008-2015
measure: Overall survival
timeFrame: 2008-2015
measure: Overall response rate
timeFrame: 2008-2015
measure: Response rates in and survival times in biological subgroups
timeFrame: 2008-2015
measure: Toxicity rates
timeFrame: 2008-2015
measure: Quality of life
timeFrame: 2008-2015
measure: Standard safety analysis
timeFrame: 2008-2015
Other outcomes:
Locations:
city: Cologne
country: Germany
facility: Medizinische Universitaetsklinik I at the University of Cologne
Study officials:
affiliation: Medizinische Universitaetsklinik I at the University of Cologne
name: Barbara Eichhorst, MD
role: PRINCIPAL_INVESTIGATOR
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