• Patients must have histological or cytological evidence of primary central nervous system (CNS) lymphoma (PCNSL); patients with vitreo-retinal lymphoma (NHL) or cerebrospinal fluid (CSF) positive disease are eligible providing there is CNS involvement on MRI compatible with PCNSL

• Patients must be 18 years of age or older

• Patients must be ineligible (≥65 years old or comorbidities) for high-dose chemotherapy and autologous stem cell transplantation. Patients must be considered fit, as determined by the treating physician, to receive high dose methotrexate, ibrutinib and rituximab as per protocol

• Patients must have consented to the release of a tumour block from their brain tumour, if available (see Section 12.0). The centre/pathologist must have agreed to the submission of the specimen(s).

• Presence of radiological documented disease. Patients believed to have residual disease following a complete resection, even if radiology is negative or equivocal, are eligible provided they are planned for standard of care methotrexate/rituximab.

• No prior systemic therapy other than the following situations:

‣ Methotrexate +/- rituximab: Patients may have received one cycle of methotrexate with or without rituximab as standard of care therapy, but must be enrolled no longer than 4 weeks after first dose of methotrexate corticosteroids for PCNSL is permitted.

⁃ Use of corticosteroids (topical are permitted) on study (except for short-term treatment of infusion reactions and nausea prophylaxis) is not permitted. Patients receiving corticosteroids me be eligible, providing:

• they are receiving not more than dexamethasone 8mg/day (or equivalent)

• The corticosteroid will be tapered and completely discontinued within 7 days of starting the study protocol treatment. Patients who would require continued or concurrent treatment with systemic steroids are not eligible.

• Intrathecal therapy: Patients may have received intrathecal therapy at the time of diagnostic lumbar puncture. No washout period is needed prior to enrollment.

• Previous major surgery is permitted provided that surgery occurred at least 28 days prior to patient enrollment and that wound healing has occurred. The 28 day cut-off does not apply to surgery for PCNSL; treatment may begin following brain biopsy/resection when deemed safe by the treating investigator

• No prior radiation therapy for PCNSL is allowed

• ECOG performance status 0-2, and ECOG 3 permitted if secondary to primary CNS lymphoma and expected to reverse with treatment

• Patients must be able to swallow oral medications and have no known gastrointestinal disorders that may interfere with absorption (such as malabsorption).

• Patients must have adequate organ and marrow function measured within 7 days prior to enrollment including: Absolute neutrophils ≥ 1.0 x 10\^9/L (independent of growth factor support); Platelets ≥ 75 x 10\^9/L; Bilirubin ≤ 1.5 x UNL; ALT ≤ 3.0 x UNL (if AST \>3 x UNL consult with CTG re: eligibility); Creatinine clearance ≥ 50 mL/min

• Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaire in either English or French

• Patients must be accessible for treatment and follow up. Patients enrolled on this trial must be treated and followed at the participating centre

• In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient enrollment

• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.