Autologous Transplantation After a Rituximab/Ibrutinib/Ara-c Containing iNduction in Generalized Mantle Cell Lymphoma - a Randomized European Mcl Network Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 870
- 试验地点
- 112
- 主要终点
- Failure Free Survival
研究概览
简要总结
The primary objective of the the trial is to establish one of three study arms, as future standard based on the comparison of the investigator-assessed failure-free survival.
详细描述
Objectives and Endpoints
Primary Objective:
To establish one of three study arms, R-CHOP/R-DHAP followed by ASCT (control arm A), R-CHOP+ibrutinib /R-DHAP followed by ASCT and ibrutinib maintenance experimental arm A+I), and R-CHOP+ibrutinib /R-DHAP followed by ibrutinib maintenance experimental arm I) as future standard based on the comparison of the investigator-assessed failure-free survival (FFS).
Secondary Objectives:
- To compare the efficacy of the three treatment arms in terms of secondary efficacy endpoints
- To determine the safety and tolerability of ibrutinib during induction immuno-chemotherapy and during maintenance and to compare the safety profile of the three treatment arms in terms of secondary toxicity endpoints
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All patients must meet the following criteria:
- •Histologically confirmed diagnosis of MCL according to WHO classification
- •suitable for high-dose treatment including high-dose Ara-C
- •Stage II-IV (Ann Arbor)
- •Age ≥ 18 years and ≤ 65 years
- •Previously untreated MCL
- •At least 1 measurable lesion; in case of bone marrow infiltration only, bone marrow aspiration and biopsy is mandatory for all staging evaluations.
- •ECOG/WHO performance status ≤ 2
- •The following laboratory values at screening (unless related to MCL):
- •Absolute neutrophil count (ANC) ≥1000 cells/µL
- •Platelets ≥100,000 cells/µL
- •Transaminases (AST and ALT) ≤3 x upper limit of normal (ULN)
- •Total bilirubin ≤2 x ULN unless due to known Morbus Meulengracht [Gilbert-Meulengracht-Syndrome])
- •Creatinine ≤2 mg/dL or calculated creatinine clearance ≥ 50 mL/min
- •Written informed consent form according to ICH/EU GCP and national regulations
- •Sexually active men and women of child-bearing potential must agree to use highly effective contraceptives (eg, condoms, implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or sterilized partner) while on study; this should be maintained for 90 days after the last dose of study drug.
排除标准
- •Any potential subject who meets any of the following criteria will be excluded from participating in the study.
- •Major surgery within 4 weeks prior to randomization.
- •Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg phenprocoumon).
- •History of stroke or intracranial hemorrhage within 6 months prior to randomization.
- •Requires treatment with strong CYP3A4/5 inhibitors.
- •Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
- •Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization.
- •Known CNS involvement of MCL
- •Clinically significant hypersensitivity (eg, anaphylactic or anaphylactoid reactions to the compound of ibrutinib itself or to the excipients in its formulation)
- •Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies
- •Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody or interferon except prephase therapy according to trial protocol
- •Serious concomitant disease interfering with a regular therapy according to the study protocol:
- •Cardiac (Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification or LVEF below LLN )
- •Pulmonary (e.g. chronic lung disease with hypoxemia)
- •Endocrinological (e.g. severe, not sufficiently controlled diabetes mellitus)
- •Renal insufficiency (unless caused by the lymphoma): creatinine > 2x normal value and/or creatinin clearance < 50 ml/min)
- •Impairment of liver function (unless caused by the lymphoma): transaminases > 3x normal or bilirubin > 2,0 mg/dl unless due to morbus Meulengracht (Gilbert-Meulengracht-Syndrome)
- •Patients with unresolved hepatitis B or C infection or known HIV positive infection (mandatory test)
- •Prior organ, bone marrow or peripheral blood stem cell transplantation
- •Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer or in situ uterine cervix cancer
- •Pregnancy or lactation
- •Any psychological, familiar, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule
- •Subjects not able to give consent
- •Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial
- •Participation in another clinical trial within 30 days before randomization in this study.
研究组 & 干预措施
Standard Arm A
R-CHOP/R-DHAP: Alternating 3 cycles of R-CHOP in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP
ASCT conditioning (ASCT: autologous stemm cell transplantation) Drug: THAM or BEAM
干预措施: R-CHOP/R-DHAP (Drug)
Standard Arm A
R-CHOP/R-DHAP: Alternating 3 cycles of R-CHOP in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP
ASCT conditioning (ASCT: autologous stemm cell transplantation) Drug: THAM or BEAM
干预措施: ASCT conditioning (Drug)
Experimental Arm A+I
R-CHOP+Ibrutinib/R-DHAP: Alternating 3 cycles of R-CHOP + Ibrutinib at Days 1-19 in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP Drug: Ibrutinib (Induction)
ASCT conditioning (ASCT: autologous stemm cell transplantation) Drug: THAM or BEAM
2 years Ibrutinib Maintenance Drug: Ibrutinib (Maintenace)
干预措施: R-CHOP/R-DHAP (Drug)
Experimental Arm A+I
R-CHOP+Ibrutinib/R-DHAP: Alternating 3 cycles of R-CHOP + Ibrutinib at Days 1-19 in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP Drug: Ibrutinib (Induction)
ASCT conditioning (ASCT: autologous stemm cell transplantation) Drug: THAM or BEAM
2 years Ibrutinib Maintenance Drug: Ibrutinib (Maintenace)
干预措施: Ibrutinib (Induction) (Drug)
Experimental Arm A+I
R-CHOP+Ibrutinib/R-DHAP: Alternating 3 cycles of R-CHOP + Ibrutinib at Days 1-19 in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP Drug: Ibrutinib (Induction)
ASCT conditioning (ASCT: autologous stemm cell transplantation) Drug: THAM or BEAM
2 years Ibrutinib Maintenance Drug: Ibrutinib (Maintenace)
干预措施: ASCT conditioning (Drug)
Experimental Arm A+I
R-CHOP+Ibrutinib/R-DHAP: Alternating 3 cycles of R-CHOP + Ibrutinib at Days 1-19 in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP Drug: Ibrutinib (Induction)
ASCT conditioning (ASCT: autologous stemm cell transplantation) Drug: THAM or BEAM
2 years Ibrutinib Maintenance Drug: Ibrutinib (Maintenace)
干预措施: Ibrutinib (Maintenance) (Drug)
Experimental Arm I
R-CHOP+Ibrutinib / R-DHAP: Alternating 3 cycles of R-CHOP + Ibrutinib at Days1-19 in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP Drug: Ibrutinib (Induction)
2 years Ibrutinib Maintenance Drug: Ibrutinib (Maintenance)
干预措施: R-CHOP/R-DHAP (Drug)
Experimental Arm I
R-CHOP+Ibrutinib / R-DHAP: Alternating 3 cycles of R-CHOP + Ibrutinib at Days1-19 in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP Drug: Ibrutinib (Induction)
2 years Ibrutinib Maintenance Drug: Ibrutinib (Maintenance)
干预措施: Ibrutinib (Induction) (Drug)
Experimental Arm I
R-CHOP+Ibrutinib / R-DHAP: Alternating 3 cycles of R-CHOP + Ibrutinib at Days1-19 in cycle 1,3,5 and 3 cyles of R-DHAP in cycle 2,4,6; each 21 day cycle
Drug: R-CHOP/R-DHAP Drug: Ibrutinib (Induction)
2 years Ibrutinib Maintenance Drug: Ibrutinib (Maintenance)
干预措施: Ibrutinib (Maintenance) (Drug)
结局指标
主要结局
Failure Free Survival
时间窗: From start of treatment until stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause, whichever comes first, assessed up to 120 months.
次要结局
- Number of participants with treatment-related adverse events as assessed by CTC Version 4.03(From start of Ibrutinib treatment during induction immuno-chemotherapy and during maintenance and to compare the safety profile of the three treatment arms in terms of secondary toxicity endpoints. Through study conduction, an average of up to 30 months.)
- Progression-free survival (PFS)(PFS is the time to progression or death from any cause. Assed up to 120 months.)
- Number of Adverse Events by CTC grade (Version 4.03)(From start of treatment through the study conduction, up to 120 months.)
- Overall Survival(From start of treatment until the date of first documented progression, assessed up to 120 months.)
- Number of Secondary Primary Malignancies(From start of treatment through the study conduction, up to 120 months.)
研究者
Prof. Dr. M. Dreyling (co-chairman)
Sponsor Delegated Person / Coordinating Prinicipal Investigator
European Mantle Cell Lymphoma Network