Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia (LLC2007SA)
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
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.
연구 개요
상세 설명
OBJECTIVES:
Primary
- 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.
Secondary
- 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.
연구 유형
등록 (실제)
단계
- 3단계
연락처 및 위치
연구 장소
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TOURS Cedex, 프랑스, 37044
- French Innovative Leukemia Organization
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Inclusion criteria
- B-CLL
- Matutes score 4 or 5
- Binet stages B or C
- Age > 65 years old
- No previous treatment of CLL by chemotherapy, radiotherapy or immunotherapy, except glucocorticoids < 1 month
- Patient's written informed consent
- Life expectancy > 6 months
Exclusion criteria
- Binet stage A
- ECOG performance status 2 or more
- Presence of a 17p deletion by FISH (> 10% positive cores)
- Clinically significant auto-immune cytopenia, Coombs-positive hemolytic anemia as judged by the treating physician
- Patients with a history of another malignancy in complete remission less than 5 years, except basal cell skin cancer or tumor treated curatively by surgery
- Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
- Any severe co-morbidities such as NYHA Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarrhythmias requiring ongoing treatment, severe uncontrolled myocardiopathy, uncontrolled hypertension, severe chronic obstructive pulmonary disease with hypoxemia, or uncontrolled diabetes mellitus.
- CIRS (Cumulative Illness rating Scale) > 6
- Known hypersensitivity to murine proteins or to any of the study drugs or to their components
- Transformation into an aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma) or prolymphocytic leukemia
- Active bacterial, viral or fungal infection
- Seropositivity HIV, hepatitis C or hepatitis B (unless clearly due to vaccination)
- Total bilirubin, alkaline phosphatases and aminotransferases > 2 x ULN
- Creatinine clearance < 60 ml/min calculated according to the formula of Cockcroft and Gault
- Any coexisting medical or psychological condition that would preclude participation to the required study procedures
- Patient with mental deficiency preventing proper understanding of the requirements of treatment
Inclusion criteria at randomization
- Patients having received the full induction phase with 4 FC and 6 rituximab courses (with/without dose adjustments as per protocol)
- Complete or partial response according to NCI and iwCLL criteria at the end of induction phase
- Recovery from FCR toxicities
- Patient willingness to continue on protocol
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 무작위
- 중재 모델: 병렬 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
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간섭 없음: Observation
Observation every 8 weeks during 2 years
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실험적: rituximab arm
rituximab :500 mg/m² every 8 weeks during 2 years
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rituximab :500 mg/m² every 8 weeks during 2 years
다른 이름들:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Progression-free survival
기간: randomization until disease progression or death
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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
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randomization until disease progression or death
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Event-free survival
기간: randomization until disease progression, death, new CLL treatment, and secondary cancer
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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
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randomization until disease progression, death, new CLL treatment, and secondary cancer
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Disease-free survival
기간: first documented CR until relapse
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Disease-free survival is defined as the time from first documented CR to relapse
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first documented CR until relapse
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Overall survival
기간: randomization until death
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Overall survival is defined as the time from randomization to death from any cause
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randomization until death
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Time to next treatment
기간: randomization until new CLL treatment
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Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment
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randomization until new CLL treatment
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Overall response rate
기간: baseline up to approximately 66 months
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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
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baseline up to approximately 66 months
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Phenotypic response rate
기간: randomization up to approximately 60 months
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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
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randomization up to approximately 60 months
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Rates of treatment-related adverse events
기간: safety since baseline
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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
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safety since baseline
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Pharmacokinetics of rituximab
기간: baseline up to approximately 36 months
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Pharmacokinetics of rituximab during induction and rituximab maintenance
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baseline up to approximately 36 months
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Quality of life
기간: baseline up to approximately 30 months
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Change from baseline in EORTC Quality of Life Questionnaire Core 30
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baseline up to approximately 30 months
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공동 작업자 및 조사자
수사관
- 수석 연구원: Caroline Dartigeas, MD, Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE
- 수석 연구원: Eric VAN DEN NESTE, MD PhD, Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM
간행물 및 유용한 링크
연구 기록 날짜
연구 주요 날짜
연구 시작
기본 완료 (실제)
연구 완료 (실제)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (추정)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- CDR0000589684
- CHRUT-LLC-2007-SA (기타 식별자: CHU Tours)
- CHRUT-PHRN05-CD (기타 식별자: CHU Tours)
- INCA-RECF0497 (기타 식별자: INCA)
- 2007-001015-28 (EudraCT 번호)
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
미국에서 제조되어 미국에서 수출되는 제품
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Rituximab에 대한 임상 시험
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Cancer Research UKBioInvent International AB; Bloodwise완전한
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Papworth Hospital NHS Foundation Trust완전한
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German High-Grade Non-Hodgkin's Lymphoma Study...Deutsche Krebshilfe e.V., Bonn (Germany)완전한
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Aprea Therapeutics종료됨맨틀 세포 림프종 | 만성림프구성백혈병 | 비호지킨 림프종미국