Ibrutinib Combination Therapy in Transplant Ineligible Individuals With Newly Diagnosed Primary CNS Lymphoma

Inclusion Criteria: 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). No prior systemic therapy other than corticosteroids for PCNSL is permitted. Use of corticosteroids to control symptoms of PCNSL is allowed, but the patient must be on a maximum dose of dexamethasone 8mg/day (or equivalent) or less at the time of enrolment. Patients must wean off the steroids within 7 days of starting the study protocol treatment 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 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; Platelets ≥ 75 x 10^9/L; Bilirubin ≤ 1.5 x UNL; ALT ≤ 2.5 x UNL; 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. Exclusion Criteria: Patients with secondary central nervous system non-Hodgkin lymphoma (NHL). Patients with significant third space accumulation (pleural effusions, ascites) which cannot be adequately drained in advance of methotrexate administration Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. However, patients on active anticancer therapy for other advanced or metastatic malignancies are not eligible. Patients with a known hypersensitivity to the study drugs or their components Patients with active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to protocol Patients may not receive concurrent treatment with other anti-cancer therapy or investigational agents while on protocol therapy Patients with prior allogenic bone marrow transplant or double umbilical cord blood transplantation. Pregnant or breastfeeding women Patients requiring: Anticoagulation with warfarin or equivalent vitamin K antagonists Continued requirement for therapy with a strong CYP3A inhibitor or inducer (see trial webpage for list) Corticosteroid treatment with > 8mg of dexamethasone (or equivalent) at the time of enrollment Supplements containing fish oil or vitamin E, and grapefruit juice should be avoided Live attenuated vaccination administered within 30 days prior to enrollment Patients with clinically significant cardiac disease, including: angina pectoris, symptomatic pericarditis, coronary artery bypass grafting, coronary angioplasty, or stenting, or myocardial infarction in the previous 12 months; history of documented congestive heart failure (New York Heart Association functional classification III-IV) or cardiomyopathy; uncontrolled hypertension (per Canadian guidelines); atrial or ventricular arrhythmias; patients with controlled atrial fibrillation are eligible Patients with distant clinically significant cardiac history should have a LVEF ≥ 50%