Generalized mantle cell Lymphoma MedDRA version: 21.0 Level: PT Classification code 10026805 Term: Mantle cell lymphoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10026804 Term: Mantle cell lymphoma stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10026803 Term: Mantle
Conditions
Sponsors
Klinikum der Universität München, Medizinische Klinik und Poliklinik III
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed diagnosis of MCL according to WHO classification 2. suitable for high-dose treatment including high-dose AraC 3. Stage II-IV (Ann Arbor) 4. Age >= 18 years and =1000 cells/uL - Platelets >=100,000 cells/uL - Transaminases (AST and ALT) = 50 mL/min 9. Written informed consent form according to ICH/EU GCP and national regulations 10. 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 and 12 months after the last dose of rituximab. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 870 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: 1. Major surgery within 4 weeks prior to randomization. 2. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg phenprocoumon). 3. History of stroke or intracranial hemorrhage within 6 months prior to randomization. 4. Requires treatment with strong CYP3A4/5 inhibitors. 5. 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. 6. Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization. 7. Known CNS involvement of MCL. 8. Clinically significant hypersensitivity (eg, anaphylactic or anaphylactoid reactions to the compound of ibrutinib itself or to the excipients in its formulation). 9. Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies. 10. Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody or interferon except prephase therapy according to trial protocol. 11. 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 3x normal or bilirubin > 2,0 mg/dl unless due to morbus Meulengracht (Gilbert-Meulengracht-Syndrome). 12. Positive test results for chronic HBV infection (defined as positive HBsAg serology (mandatory testing). Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing.Patients who have protective titers of hepatitis B Surface antibody (HBSAb) after vaccination are eligible. 13. Positive test results for hepatitis C (mandatory hepatitis C virus HCV antibody serology testing). Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 14. Patients with known HIV positive infection (mandatory test). 15.Prior organ, bone marrow or peripheral blood stem cell transplantation. 16. Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer or in situ uterine cervix cancer. 17.Pregnancy or lactation. 18. Any psychological, familiar, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule. 19. Subjects not able to give consent. 20. Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial. 21. Participation in another clinical trial within 30 days before randomization in this study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main 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 armA+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 Objective: 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 end point(s): FFS defined as time from randomization to stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause. ;Timepoint(s) of evaluation of this end point: End of immuno-chemotherapy, progressive disease, or death from any cause | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Efficacy Endpoints: 1. Overall survival (OS). 2. 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). 3. Overall response and complete remission rates at midterm, at end of induction, 3 months after end of induction immunochemotherapy (at month 6). 4. PR to CR conversion rate during follow-up after end of induction immuno-chemotherapy. Secondary Toxicity Endpoints: 1. 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. 2. Cumulative incidence rates of SPMs. ;Timepoint(s) of evaluation of this end point: See E.5.2 | — |
Countries
Belgium, Croatia, Czechia, Czech Republic, Denmark, Finland, Germany, Israel, Italy, Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, United Kingdom
Contacts
Public ContactHead of Study Center for Hematology
Klinikum der Universität München, Medizinische Klinik und Poliklinik III
Outcome results
None listed