Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia (LLC2007SA)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT00645606|
Recruitment Status : Completed
First Posted : March 27, 2008
Last Update Posted : August 1, 2017
RATIONALE: Classical chemotherapy does not cure advanced chronic lymphocytic leukemia (CLL) despite new drugs. Rituximab is a monoclonal antibody directed against CD20 surface antigen on B lymphocytes and leads to apoptosis of CD20 positive B lymphocytes. The highest response rate yet published in the treatment of first-line CLL has been obtained by the association of fludarabine, cyclophosphamide and rituximab (FCR). Now, the question is whether this response can be improved, as some trials showed that eradication of minimal residual disease (MRD) in CLL is associated with a longer treatment-free and overall survival. Maintenance therapy using rituximab has been recently approved as a means of prolonging remission in patients with indolent non Hodgkin's lymphoma. Maintenance therapy with rituximab could be of interest in treatment of MRD in CLL and prolonging remission and survival times.
PURPOSE: The overall purpose of the study is to determine the value of immunotherapy maintenance with single agent rituximab in comparison with no further treatment (observation ) for previously untreated chronic lymphocytic leukaemia in elderly (>65 years) patients who respond to induction immunochemotherapy with FCR.
|Condition or disease||Intervention/treatment||Phase|
|Leukemia||Biological: Rituximab||Phase 3|
- To demonstrate superiority, in terms of 3-year progression-free survival (PFS), of rituximab maintenance over observation in patients who are in complete or partial response (CR or PR) after induction therapy comprising fludarabine, cyclophosphamide, and rituximab.
- To determine event-free survival, disease-free survival, overall survival, and time to next treatment, all from time of randomization.
- To determine overall response rate (CR and PR) according to NCI and iwCLL criteria
- To assess the rate of phenotypic response (minimal residual disease).
- To assess duration of phenotypic and NCI and iwCLL clinical responses.
- To determine response rates and time-related parameters in biological subgroups.
- To determine rates of treatment-related adverse events.
- To evaluate CD4/CD8 counts, immunoglobulin levels, and incidence of Coombs-positive hemolytic anemia.
- To study pharmacokinetics of rituximab during induction and maintenance.
- To evaluate the prognostic impact of the immunoglobulin FcγRIIIA genotype.
- To assess quality of life.
- To study pharmacoeconomics.
OUTLINE: This is a multicenter study. Randomization is stratified according to response to induction therapy (complete response [CR] vs partial response [PR]), IGHV mutational status, and 11q deletion.
Patients receive rituximab IV on days 1 and 14 of courses 1-2 and on day 1 of courses 3 and 4. Patients also receive oral fludarabine and oral cyclophosphamide once daily on days 2-4 of course 1 and on days 1-3 of courses 2-4. Courses are administered every 28 days. Patients achieving CR or PR are randomized 1:1 to maintenance arm or observation arm.
- Arm A: Patients receive rituximab IV every 2 months in the absence of disease progression or unacceptable toxicity for a maximum duration of 24 months (12 infusions).
- Arm B: Patients undergo observation only.
After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 2 years.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||542 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Single-agent Rituximab as Maintenance Treatment Versus Observation After Combined Induction Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab in Patients Older Than 65 Years With Previously Untreated Chronic Lymphocytic Leukemia: a Phase III Trial of FILO|
|Study Start Date :||December 2007|
|Actual Primary Completion Date :||February 2014|
|Actual Study Completion Date :||July 2017|
No Intervention: Observation
Observation every 8 weeks during 2 years
Experimental: rituximab arm
rituximab :500 mg/m² every 8 weeks during 2 years
rituximab :500 mg/m² every 8 weeks during 2 years
Other Name: Mabthera
- Progression-free survival [ Time Frame: randomization until disease progression or death ]Progression-free survival is defined as the time from randomization to the first occurrence of disease progression, relapse or death from any cause; using iwCLL criteria
- Event-free survival [ Time Frame: randomization until disease progression, death, new CLL treatment, and secondary cancer ]Event-free survival is defined as the time from randomization to the occurrence of one of the following events, whichever occurs first: disease progression or relapse, death from any cause, initiation of any new anti-CLL therapy, and secondary malignancy
- Disease-free survival [ Time Frame: first documented CR until relapse ]Disease-free survival is defined as the time from first documented CR to relapse
- Overall survival [ Time Frame: randomization until death ]Overall survival is defined as the time from randomization to death from any cause
- Time to next treatment [ Time Frame: randomization until new CLL treatment ]Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment
- Overall response rate [ Time Frame: baseline up to approximately 66 months ]Overall response rate is defined by the percentage of participants with an overall response; CR or PR according to NCI criteria and CR, CRi or PR according to iwCLL
- Phenotypic response rate [ Time Frame: randomization up to approximately 60 months ]Phenotypic response rate is defined by the percentage of participants with minimal residual disease negativity as measured by six-colour flow cytometry with a sensitivity of 0.7 x 10-5. MRD is considered as undetectable when the positivity criteria, defined as the presence of at least 20 CLL cells, is not reached
- Rates of treatment-related adverse events [ Time Frame: safety since baseline ]Rate of treatment-related adverse events (plus adverse events of particular interest) is defined as the percentage of participants with adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and version 2.0. for hematological toxicity
- Pharmacokinetics of rituximab [ Time Frame: baseline up to approximately 36 months ]Pharmacokinetics of rituximab during induction and rituximab maintenance
- Quality of life [ Time Frame: baseline up to approximately 30 months ]Change from baseline in EORTC Quality of Life Questionnaire Core 30
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00645606
|French Innovative leukemia Organization|
|TOURS Cedex, France, 37044|
|Principal Investigator:||Caroline Dartigeas, MD||Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE|
|Principal Investigator:||Eric VAN DEN NESTE, MD PhD||Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM|