ASCT After a Rituximab/Ibrutinib/Ara-c Containing iNduction in Generalized Mantle Cell Lymphoma

Autologous Transplantation After a Rituximab/Ibrutinib/Ara-c Containing iNduction in Generalized Mantle Cell Lymphoma - a Randomized European Mcl Network Trial

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.

Inclusion Criteria:

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.

Exclusion Criteria:

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.