Clinical Trial Finder

Inclusion Criteria:

1. Newly diagnosed Primary Central Nervous System Lymphoma (PCNSL). 2. a) Aged between 18 and 60 (>18 and < 60)

• - phase IB b) Aged between 18 and 65 (≥ 18 and ≤ 65) - phase II.

3. Histological confirmed diagnosis of Primary central nervous system lymphoma of Diffuse Large B-Cell Lymphomas (DLBCL) type OR patients with a measurable typical cerebral lesion on MRI with a diagnosis made by cytology and/or by flow cytometry on the vitreous or on the cerebral spinal fluid. 4. Measurable lesion on MRI with gadolinium enhancement. 5. Adequate hematological, renal and hepatic function (Laboratory Parameters realized within 14 days before inclusion): 1. Absolute neutrophil count (ANC) >1000/mm3. 2. Platelets > 100,000/mm3 independent of transfusion support. 3. Alanine aminotransferase and aspartate aminotransferase ≤ 3 x Upper Limit of Normal (ULN) 4. Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin. 5. Estimated Glomerular Filtration Rate ≥ 60 mL/min/1.73m2. 6. Able to swallow capsules. 7. Karnofsky performance status: 40-100% for the phase IB and no restriction on the KPS for the phase

• II. 8.

Able to understand teratogenic risks of the Lenalidomide and Ibrutinib. Patient must be able to understand and fulfill the Lenalidomide Pregnancy Prevention Plan requirements. This plan may be accepted by the person of confidence in case of impaired cognitive status of the patient. 9. Women of childbearing potential (WCBP)* and men who are sexually active must be practicing a highly effective method** of birth control. Women should avoid a pregnancy while taking treatment by Lenalidomide or Ibrutinib and for up to 1 month after ending treatment. Men must agree to not to father a child or donate sperm during treatment by Lenalidomide or Ibrutinib and up to 3 months after the last dose of study drug. 10. Women of childbearing potential (WCBP)* must have a negative serum (beta-human chorionic gonadotropin [B-hCG]) or urine pregnancy test at inclusion. 11. Signed informed consent, which could be signed by a person on confidence in case the neurologic status of the patient does not allow him to understand and/or to sign.

Exclusion Criteria:

1. Histology other than DLBCL. 2. Positive HIV serology. 3. Active viral infection with Hepatitis B or C virus. 4. Preexisting immunodeficiency and/or organ transplant recipient. 5. Isolated Central Nervous System (CNS) relapse of systemic Non-Hodgkin's Lymphoma. 6. Prior treatment for PCNSL (except corticosteroids). 7. Isolated primary vitreo-retinal lymphoma. 8. Major surgery, within 4 weeks prior to the first dose of study drug. Stereotactic biopsy and vitrectomy are not considered major surgery. 9. History of stroke or intracranial hemorrhage (except minor post biopsy hemorrhage) within 6 months prior to inclusion. 10. Requires anticoagulation with warfarin or equivalent vitamin K antagonists. 11. Requires treatment with strong CYP3A4 inhibitors. 12. Pregnancy or lactation. 13. Clinically significant cardiovascular disease. 14. Any other active malignancy, except basocellular carcinoma and non-invasive cervix cancer. 15. Inclusion in another experimental anti-cancer drug therapy. 16. No social security affiliation. 17. Persons under legal protection.

The objective of this proposal is to test the feasibility and efficacy of two targeted induction chemotherapies obtained by adding either Lenalidomide or Ibrutinib to a standard Rituximab-High Dose (HD) Methotrexate (MTX) based induction chemotherapy regimen. The R-MPV regimen is chosen as the backbone chemotherapy because of its wide use with robust reproducible results and a good and manageable toxicity profile

Arms

Active Comparator: Arm A: R-MPV with Lenalidomide

Lenalidomide in association with R-MPV as a targeted induction treatment

Active Comparator: Arm B: R-MPV with Ibrutinib

Ibrutinib in association with R-MPV as a targeted induction treatment

Interventions

Drug: - Lenalidomide

Patients will receive 4 cycles of induction chemotherapy with R-MPV + Lenalidomide using the Maximum Tolerated Dose (MTD) of Lenalidomide and Ibrutinib as determined in the phase-Ib part of the study.

Drug: - Ibrutinib

Patients will receive 4 cycles of induction chemotherapy with R-MPV + Ibrutinib, using the Maximum Tolerated Dose (MTD) of Lenalidomide and Ibrutinib as determined in the phase-Ib part of the study.