Bruton's Tyrosine Kinase (BTK) Inhibition in B-cell Lymphomas

Inclusion Criteria:

1. Patients with any type of relapsed or refractory B-cell lymphoma will be eligible in groups A, A bis, B and B bis (during the dose escalation and the expansion parts of the study) and untreated patients with mantle cell lymphoma will be eligible for group C (only during the expansion part of the study)
2. Each patient (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study
3. Patients eligible for autologous stem cell transplantation (ASCT) for whom R-DHAP or R-DHAOx is an acceptable therapy regarding the investigator's opinion
4. Measurable disease defined by at least one single node or tumor lesion \> 1.5 cm
5. Patients who received prior therapy with at least one but no more than two lines therapies for B-Cell Lymphoma (except for patients included in group C during the expansion part of the study)
6. Aged between 18 years and 70 years (included)
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
8. Any of the following hematology values within 14 days prior to inclusion and prior to the first dose of study drug :

   1. Absolute neutrophil count (ANC) \> 1,000 cells/mm3 (1.0 x 109/L) unless if bone marrow infiltration from lymphoma
   2. Spontaneous Platelets count \> 75,000 cells/mm3 (75 x 109/L) within 7 days of any platelet transfusion (allowed up to 50 x 109/L if due to bone marrow infiltration from lymphoma)
9. Patients assessed as being able to receive full doses of R-DHA(P/Ox) for 3 cycles or 4 cycles for patients included in group C of the expansion phase
10. Life expectancy of ≥ 90 days (3 months)
11. Women of childbearing potential\* and men who are sexually active must be practicing a highly effective method of birth control during the study and during 12 months after the end of treatments. Men must agree to not donate sperm during the study and during 12 months after the end of treatments
12. Women of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-hCG) or urine pregnancy test at Screening

Exclusion Criteria:

1. Previous treatment with a BTK inhibitor
2. Patients who progressed or became refractory while on treatment with a phosphoinositide 3-kinase (PI3K) inhibitors
3. Inability to tolerate 4 courses of high dose ara-C / platin compound, especially if due to underlying comorbidities
4. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug
5. Major surgery, within 4 weeks prior to the first dose of study drug
6. Known bleeding diathesis
7. Condition that requires therapeutic anticoagulation with Vitamin K antagonists
8. Condition that requires treatment with a strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitor
9. Any life-threatening illness, serious medical condition, laboratory abnormality, organ system dysfunction or psychiatric illness which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk and that would prevent the patient from signing the informed consent form
10. Known central nervous system or meningeal involvement by lymphoma
11. Contraindication to any drug contained in these regimen
12. Known history of human immunodeficiency virus (HIV)
13. Known active Hepatitis C Virus (HCV; RNA polymerase chain reaction (PCR)-positive) or active Hepatitis B Virus infection (HBs Ag positive or DNA PCR-positive) or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics. Patients with PCR-negative for hepatitis B virus (HBV) are permitted in the study.
14. Left ventricular ejection fraction (LVEF) \< 45% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan
15. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
16. Any of the following biochemical values within 14 days prior to inclusion and prior to the first dose of study drug :

    1. Serum glutamic-oxaloacetic transaminase/aspartate aminotransferase (SGOT/ASAT) or serum glutamic-pyruvic transaminase/alanine aminotransferase (SGPT/ALAT) \> 3.0 x upper limit of normal (ULN)
    2. Serum total bilirubin \> 2.0 mg/dL (34 µmol/L), except in patients with hemolytic anemia or with Gilbert syndrome,
    3. Calculated creatinine clearance of \< 50 mL /min (for patients who will have DHAOx chemotherapy) or \< 70 mL/min (for patients who will have DHAP chemotherapy)
17. Patients with pre-existing ≥ Grade 2 neuropathy
18. Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the patient has been free of the disease for ≥ 3 years
19. Use of any standard or experimental anti-cancer drug therapy within 28 days prior to the first dose of study drug
20. Women who are pregnant or breastfeeding
21. Medical history of hepatic chronic disease whatever the anteriority
22. Sinusoidal obstruction syndrome (Veno-Occlusive Disease (VOD)) whatever the anteriority