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.
調査の概要
詳細な説明
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.
研究の種類
入学 (実際)
段階
- フェーズ 3
連絡先と場所
研究場所
-
-
-
TOURS Cedex、フランス、37044
- French Innovative Leukemia Organization
-
-
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
介入なし：Observation
Observation every 8 weeks during 2 years
|
|
|
実験的：rituximab arm
rituximab :500 mg/m² every 8 weeks during 2 years
|
rituximab :500 mg/m² every 8 weeks during 2 years
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Progression-free survival
時間枠：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
|
randomization until disease progression or death
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Event-free survival
時間枠：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
|
randomization until disease progression, death, new CLL treatment, and secondary cancer
|
|
Disease-free survival
時間枠：first documented CR until relapse
|
Disease-free survival is defined as the time from first documented CR to relapse
|
first documented CR until relapse
|
|
Overall survival
時間枠：randomization until death
|
Overall survival is defined as the time from randomization to death from any cause
|
randomization until death
|
|
Time to next treatment
時間枠：randomization until new CLL treatment
|
Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment
|
randomization until new CLL treatment
|
|
Overall response rate
時間枠：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
|
baseline up to approximately 66 months
|
|
Phenotypic response rate
時間枠：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
|
randomization up to approximately 60 months
|
|
Rates of treatment-related adverse events
時間枠：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
|
safety since baseline
|
|
Pharmacokinetics of rituximab
時間枠：baseline up to approximately 36 months
|
Pharmacokinetics of rituximab during induction and rituximab maintenance
|
baseline up to approximately 36 months
|
|
Quality of life
時間枠：baseline up to approximately 30 months
|
Change from baseline in EORTC Quality of Life Questionnaire Core 30
|
baseline up to approximately 30 months
|
協力者と研究者
捜査官
- 主任研究者：Caroline Dartigeas, MD、Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE
- 主任研究者：Eric VAN DEN NESTE, MD PhD、Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- CDR0000589684
- CHRUT-LLC-2007-SA (その他の識別子：CHU Tours)
- CHRUT-PHRN05-CD (その他の識別子：CHU Tours)
- INCA-RECF0497 (その他の識別子：INCA)
- 2007-001015-28 (EudraCT番号)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
米国で製造され、米国から輸出された製品。
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