Ibrutinib and Standard Immuno-Chemotherapy in Younger, High-Risk Patients With Diffuse Large B-Cell Lymphoma

Prior treatment

• Vaccinated with live, attenuated vaccines within 4 weeks of inclusion.
• Major surgery within 4 weeks of inclusion.
• Any prior lymphoma-directed therapy (except pre-phase treatment).
• Requires treatment with strong CYP3A inhibitors.
• Concurrent treatment with other investigational agent or X-ray therapy.
• Previous chemo- or radiotherapy for any other malignancy, in particular indolent lymphoma.

Other illness

• Diagnosed or treated for malignancy other than diffuse large B-cell lymphoma, in particular any other (indolent) lymphoma.
• 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 or 4 cardiac disease as defined by the New York Heart Association Functional classification.
• History of stroke or intracranial hemorrhage within six months of inclusion.
• Known history of human immunodeficiency virus or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection requiring IV antibiotics.
• 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.
• Any psychological, cognitive, familial, sociological or geographical condition that, in the investigator's opinion, compromises the patient's ability to understand the patient information, to give informed consent or to comply with the study protocol.

Other

• Known central nervous system involvement.
• Bone marrow involvement \> 25%
• Requires anticoagulation with warfarin or equivalent vitamin K antagonist.
• Use of preparations containing St. John's Wort.
• Participation in another interventional clinical trial during this trial. There may be exceptions at the discretion of the coordinating investigator.

• Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
• Age between 18-60 years
• Risk score 2 or 3 according to age-adjusted International Prognostic Index
• Histology: Primary diagnosis of diffuse large B-cell lymphoma
• Performance status: ECOG (toxicity and response criteria of the eastern cooperative oncology group) 0-3
• Stage: all stages according Ann Arbor
• Absolute neutrophil count: \> 1000 cells/microliter (independent of growth factor support)
• Platelet count ≥ 100.000/mm³ or ≥ 50.000/mm³ if bone marrow involvement independent of transfusion support in either situation.
• Alanine-aminotransferase and Aspartate-aminotransferase: \< 3 x Upper limit of normal value
• Total Bilirubin: \< 1.5 x Upper limit of normal value
• Serum Creatinine: \< 2 x Upper limit of normal value or estimated Glomerular filtration rate (Glomerular filtration rate \[Cockcroft-Gault\]) ≥ 40 ml/min
• Women of childbearing potential and men who are sexually active must be practising a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For male subjects, these restrictions apply for 6 months after last dose of study drug. For female subjects, they apply for 12 months after last dose of study drug.
• Women of childbearing potential must have negative serum or urine beta-human chorionic gonadotropin pregnancy test at screening. Women who are pregnant or breast-feeding are ineligible for this study.
• Willing/ able to adhere to the prohibitions and restrictions specified in this protocol.