The study is an open label, prospective, multicenter, phase II study which aims to define ibrutinib efficacy in patients with relapsed or refractory primary central nervous lymphoma (PCNSL) or intraocular lymphoma (IOL) as measured by the disease control (DC) rate (complete response (CR) + uncertain complete response (Ru) + partial response (PR) stabilized disease (SD)) after 2 cycles of treatment according to International study group for PCNSL (IPCG) criteria.

Inclusion Criteria:

1. Histologically confirmed diagnosis of PCNSL or cytologically proven diagnosis of IOL or lymphomatous meningitis of B-cell type. In case of CNS lymphoma relapse or refractory PCNSL, cerebral biopsies are not required if imaging reveals typical images of PCNSL. In case of isolated IOL relapse, vitrectomy is not required if i) vitrectomy was part of the initial diagnosis workout, and ii) ocular examination and dosage of IL-10 in the anterior chamber of the eye performed at relapse or progression are highly in favour of IOL relapse (> 50 pg/ml in aqueous humor or 400 pg/ml in vitreous).
2. Aged 18 years and older.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2.
4. Life expectancy ≥ 3 months.
5. No more than 4 lines of anti-cancer treatment received.
6. Patients must have recovered within 28 days to a grade ≤ 1 from all toxicities related to prior treatments.
7. Adequate Laboratory Parameters within 14 days:
8. Measurable PCNSL as diagnosed on MRI
9. Highly effective method of birth control during and after the study consistent. Men must agree to not donate sperm during and after the study. These restrictions apply for 1 year after the last dose of study drug.
10. Women of childbearing potential must have a negative serum beta-hCG or urine pregnancy test at Screening.
11. Sign of an informed consent document.The informed consent document can be signed by a person of confidence in case neurologic disorders related to the disease prevent the patient to sign himself.

Exclusion Criteria:

1. Contraindication to any excipients of the drug.
2. T-cell lymphoma.
3. 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), prior history of systemic lymphoma, unless the patient has been free of the disease for ≥ 3 years.
4. Prior history of organ transplantation or other cause of severe immunodeficiency.
5. Major surgery, within 4 weeks prior to the first dose of study drug.
6. History of stroke or intracranial hemorrhage within 6 months prior to randomization. Patients with post-biopsies hemorrhagic sequela defined as a small hyperdense lesion < 3 mm on T2* sequence won't be excluded.
7. Requires anticoagulation with warfarin or equivalent vitamin K antagonists or ongoing warfarin medication or other equivalent vitamin K antagonists.
8. Any anti-platelet aggregant medication except acetyl salicylic acid ≤ 75 mg/day.
9. Requires treatment with strong CYP3A4 inhibitors.
10. 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 Class 4 cardiac disease as defined by the New York Heart Association Functional Classification.
11. Vaccinated with live, attenuated vaccines within 4 weeks prior to the first dose of study drug.
12. Known history of HIV or active Hepatitis C Virus (HCV; RNA polymerase chain reaction [PCR]-positive) or active Hepatitis B Virus (HBs Ag positive or DNA PCR-positive) infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
13. Any life-threatening illness, medical condition, or organ system dysfunction which could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
14. Inability to swallow capsules.
15. Pregnancy or lactation.
16. Use of anti-cancer drug therapy within 21 days prior to the first dose of study drug.
17. Previous treatment by BTK inhibitors and PI3K inhibitors.
18. Known bleeding diathesis.
19. Inclusion in another experimental anti-cancer drug therapy*.
20. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.
21. Patient under measure of legal protection.
22. No social security affiliation.