ANSM decision due to veino occlusive disease (security alert)

This is an open label, multicenter, dose escalation, phase Ib study to determine the recommended dose by assessing the maximum tolerated dose (MTD), safety and efficacy of ibrutinib in combination with R-DHAP (Group A/Abis) or R-DHAOx (Group B/Bbis) for patients with B-cell malignancies. This dose escalation will be followed by an exploratory expansion phase in 3 groups of 12 patients each (Group A/Abis, Group B/B bis and Group C).

During Part 1 Dose Escalation, the "3+3" design will be applied. Three doses of ibrutinib (280, 420 and 560 mg) will be examined sequentially in each cohort by the Dose Escalation Committee. Dose escalation will begin at dose level 1 = 420 mg.

The dose escalation will be performed for two types of associations in five separate groups :

• Group A : ibrutinib D1-D21+ R-DHAP
• Group B : ibrutinib D1-D21 R-DHAOx
• Group Abis : ibrutinib D5-D18+ R-DHAP
• Group Bbis : ibrutinib D5-D18 R-DHAOx

This dose escalation will be followed by an exploratory expansion phase in the group Bbis plus a new group including only mantle cell lymphoma (MCL) in first line patients: group C. Patients included in the Group C will receive ibrutinib in combination with R-DHAP or R-DHAOx according to the choice of the local investigator at time of inclusion of each patient.

The primary objective of this study is to determine the recommended dose of ibrutinib when administered in combination with R-DHAP (rituximab + dexamethasone + cytarabine + cisplatin) or with R-DHAOx (rituximab + dexamethasone + cytarabine + oxaliplatin) in patients with relapsed or refractory B-cell malignancies eligible for autologous stem cell transplantation (ASCT) by assessing the maximum tolerated dose (MTD) observed during the dose escalation part of the study. Assessment of the MTD will be performed by the analysis of the dose-limiting toxicities (DLTs).

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