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.
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 Primary Endpoint: FFS defined as time from start of treatment to stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause. Secondary Efficacy Endpoints: * Overall survival (OS) * Progression-free survival (PFS) from randomization, from end of induction immuno-chemotherapy in patients with CR or PR at end of induction immuno-chemotherapy, and from the staging 6 weeks after end of induction assessment (at month 6) * Overall response and complete remission rates at midterm, at end of induction, 3 months after end of induction immunochemotherapy (at month 6) * PR to CR conversion rate during follow-up after end of induction immuno-chemotherapy Secondary Toxicity Endpoints: * Rates of AEs, SAEs, and SUSARs by CTC grade (Version 4.03) during induction immuno-chemotherapy and during periods of follow-up after response to immune-chemotherapy * Cumulative incidence rates of SPMs Exploratory Objectives: * To compare feasibility of ASCT in arm A+I vs. arm A * To compare minimal residual disease status between the three treatment groups * To determine the impact of ibrutinib during induction immuno-chemotherapy and during maintenance therapy on the minimal residual disease status * To determine the prognostic value of minimal residual disease status * To determine the prognostic value of positron emission tomography with fluorine 18-fluorodeoxyglucose * To determine clinical and biological prognostic and predictive factors * To determine the role of total body irradiation (TBI) in ASCT conditioning Exploratory Endpoints: * Rate of successful stem cell mobilisations (success: separation of at least 2x2x10(6) CD34-positive cells, including a back-up) * Rate of molecular remissions (MRD-negative patients) at midterm, at end of induction immuno-chemotherapy, and at staging time-points during follow-up in patients with remission after end of induction immuno-chemotherapy * Time to molecular remission from start of therapy * Time to molecular relapse for patients in clinical and molecular remission after end of induction immunochemotherapy * RD in FDG-PET negative or positive patients after induction and ASCT Exploratory objectives may be evaluated only in a subset of patients according to local standards and resources.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
870
Drug: R-CHOP/DHAP Alternating 3x R-CHOP (Rituximab , Cyclophosphamide ,Doxorubicine ,Vincristine , Prednisone) / 3x R-DHAP (Rituximab , Dexamethasone, Ara-C, Cisplatine, G-CSF)
Ibrutinib: only in cycle 1,3,5 on Day 1-19
ASCT conditioning THAM or BEAM, stratified per site before trial activation at site THAM (TBI (total body irradiation), Ara-C, Melphalan) or BEAM (BCNU, Etoposide, Cytarabine, Melphalan)
Failure Free Survival
Time frame: 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.
Overall Survival
Time frame: From start of treatment until the date of first documented progression, assessed up to 120 months.
Number of participants with treatment-related adverse events as assessed by CTC Version 4.03
Safety and tolerability
Time frame: 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)
Time frame: PFS is the time to progression or death from any cause. Assed up to 120 months.
Number of Secondary Primary Malignancies
Toxicity Endpoints
Time frame: From start of treatment through the study conduction, up to 120 months.
Number of Adverse Events by CTC grade (Version 4.03)
Toxicity Endpoints
Time frame: From start of treatment through the study conduction, up to 120 months.
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Ibrutinib (Maintenance), daily 560 mg for 2 years;
Aalborg University Hospital, Dept of Hematology
Aalborg, Denmark
NOT_YET_RECRUITINGAarhus University Hospital, Dept of Hematology
Aarhus C, Denmark
NOT_YET_RECRUITINGRigshospitalet, Clinic of Hematology
Copenhagen, Denmark
NOT_YET_RECRUITINGHerlev Hospital, Department of Hematology L121
Herlev, Denmark
NOT_YET_RECRUITINGOdense University Hospital, Dept of Hematology X
Odense C, Denmark
NOT_YET_RECRUITINGSjaelland University Hospital, Dept of Hematology
Roskilde, Denmark
NOT_YET_RECRUITINGZentralklinik Augsburg, II. Med. Klinik, Hämatologie int. Onkologie
Augsburg, Germany
RECRUITINGOnkologische Gemeinschaftspraxis Dr. Janssen/Dr. Reichert in der Ubbo-Emmius-Klinik
Aurich, Germany
RECRUITINGKlinikum Bayreuth, Klinik f. Onkologie und Hämatologie
Bayreuth, Germany
RECRUITINGVivantes Klinikum Am Urban, Klinik f. Innere Medizin, Hämatologie und Onkologie
Berlin, Germany
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