Lenalidomide in Conjunction With Methotrexate, Leucovorin, Cytarabine and Rituximab for the Treatment of Relapsed or Refractory CD20-positive Aggressive Lymphomas: an Open-label, Multicenter Phase I/II Trial
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Dose-limiting toxicity
研究概览
简要总结
Multicenter prospective open-label non-randomised phase I/II study in patients with relapsed or refractory CD20-positive aggressive lymphomas
Phase I:
Dose escalation of methotrexate and cytarabine (days 1, 8 and 15 of each 28-day cycle) in a 3 + 3 design with fixed doses of lenalidomide (days 1 - 21) and rituximab (day 1), maximum 6 cycles
Phase II:
Treatment of 20 patients at maximum tolerated doses of phase I
详细描述
Phase I
The goal of the phase I part of the study is to determine the maximum tolerated doses of methotrexate and cytarabine able to be combined with once-per-cycle rituximab and full-dose 3-weeks-on/1-week-off lenalidomide in 28-day treatment cycles. Methotrexate and cytarabine will be given three times per cycle, preferably on days 1, 8 and 15. If short-term toxicity precludes once-per-week dosing, treatment may be delayed by a maximum of 3 days, e.g. the second injection of methotrexate and cytarabine may be delayed until day 11 and the third injection until day 21. The doses of methotrexate and cytarabine will be adjusted to permit administration of three doses per cycle without the need to postpone the subsequent treatment cycle by more than 7 days.
Dose limiting toxicity will be determined by increasing the doses of methotrexate and cytarabine in sequential patient cohorts in a 3 + 3 design. Because tolerance to lenalidomide and cytotoxic agents are likely to decrease with increasing numbers of treatment cycles, evaluation of dose-limiting toxicity will be confined to the first two cycles. The requirement for dose reductions in subsequent treatment cycles will not be rated as dose-limiting toxicity.
If no dose-limiting toxicity is observed in 3 patients treated at the same dose level, the next 3 patients will be treated at the next higher dose level. If a single patient experiences dose-limiting toxicity, another 3 patients will be treated at the same dose level. If no more than one dose-limiting toxicity is observed in 6 patients treated at that level, the next 3 patients will be treated at the subsequent dose level. If two or more of 3 - 6 patients treated at the same level experience dose-limiting toxicity, dose escalation will be stopped. The dose level below the level where dose-limiting toxicity was observed defines the maximum tolerated dose.
The dose level below the level where dose-limiting toxicity is observed defines the maximum tolerated doses of methotrexate and cytarabine. However, if, at a lenalidomide dose of 25 mg, methotrexate and cytarabine cannot be escalated beyond the first dose level, the lenalidomide dose will be reduced to 20 mg, and the methotrexate/cytarabine dose level producing dose-limiting toxicity will be repeated at a lenalidomide dose of 20 mg. If, at a lenalidomide dose of 20 mg, methotrexate and cytarabine cannot be escalated beyond the first dose level, the lenalidomide dose will be reduced to 15 mg, and the methotrexate/cytarabine dose level producing dose-limiting toxicity will be repeated with a lenalidomide dose of 15 mg. If, at a lenalidomide dose of 15 mg, methotrexate and cytarabine cannot be escalated beyond the first dose level, dose limiting toxicity is reached and the maximum tolerated dose is the highest dose of lenalidomide able to be combined with the first dose level of methotrexate and cytarabine in a 3 + 3 phase I design.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Performance status ECOG 0 - 3
- •First or subsequent relapse or refractoriness of a biopsy-proven CD20-positive aggressive B cell lymphoma (excluding mantle cell lymphoma)
- •Measurable disease
- •Ineligibility or unwillingness to undergo high-dose chemotherapy with autologous stem cell transplantation
- •Ability to understand the aim of the study and act accordingly
- •Effective contraception
- •Signed informed consent
排除标准
- •Central nervous system relapse of aggressive lymphoma
- •Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
- •Any condition including the presence of laboratory abnormalities which places the subject at unacceptable risk if he/she were to participate in the study
- •Any condition that confounds the ability to interpret data from the study
- •Inadequate organ function not related to aggressive lymphoma:
- •neutrophils < 1.0/nl
- •platelets < 75/nl
- •creatinine clearance < 60 ml/min
- •bilirubin ≥ 2,5 mg/dl
- •serum AST/GOT or ALT/GPT ≥ 4 x upper limit of normal
- •Active viral hepatitis (HBV, HCV), HIV infection, any other uncontrolled infection
- •Pregnancy and nursing period
研究组 & 干预措施
Lenalidomide
The LeMLAR protocol:
Lenalidomide 25 mg p.o., days 1 - 21; Methotrexate 30 - 60 - 90 - 120 - 150 mg/m² i.v. bolus, days 1, 8, 15; Leucovorin 4 x 45 mg p.o. (every 6 hrs), days 2, 9, 16; Cytarabine (Ara-C) 75 - 150 - 225 - 300 - 375 mg/m² i.v. bolus, days 1, 8, 15; Rituximab 375 mg/m² i.v. infusion, day 1.
28-day cycles, maximum 6 cycles, definition of dose-limiting toxicity in cycles 1 and 2, intra-patient dose escalation after cycles 2 and 4 in case of absence of dose-limiting toxicity in previous cycles
干预措施: Lenalidomide (Drug)
结局指标
主要结局
Dose-limiting toxicity
时间窗: Two months
Phase I: Dose-limiting toxicity of the combination regimen, determination of the maximum tolerated doses of methotrexate and cytarabine Phase II: Overall response rate (percentage of complete and partial remissions combined)
次要结局
- Progression-free survival(1 year)
研究者
Ulrich Duehrsen
Prof. Dr. med.
University Hospital, Essen