Background: PCNSL is an aggressive primary brain tumor. Outcome and treatment options are poor for patients with recurrent/refractory disease. Response rates range between 30-60% with a progression free survival (PFS) of 2-6 months. Ibrutinib has shown promising clinical response in some B-cell malignancies. This phase I trial investigates ibrutinib in patients with recurrent/refractory (r/r) PCNSL and secondary CNS lymphoma (SCNSL). Methods: Eligible patients had r/r PCNSL or SCNSL, age ≥ 18, KPS ≥ 50, normal end-organ function, and unrestricted number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Ten patients were enrolled (3 at 560 mg; 7 at 840 mg). Median age was 70 (range 21-80); 7 were women. Median ECOG was 1 (0: 1, 1: 5, 2: 4). 70% had PCNSL and 30% SCNSL. Six had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 1 both. Patients were highly pretreated: 2 (both SCNSL) had prior stem cell transplant; 3 (2 PCNSL, 1 SCNSL) prior radiation. The median prior CNS directed therapy was 2; all methotrexate regimens. Two patients withdrew despite clinical and radiographic response. Treatment has been well tolerated with 2 grade 4 toxicities (neutropenia and lymphopenia) that resolved after the drug was held. The most common toxicities observed were hyperglycemia, hypercholesteremia, and thrombocytopenia. After a median follow-up of 150 days, 9/10 patients were evaluated for response: 4 CR (3 in CSF; 1 in the parenchyma), 3 PR, and 2 PD; 78% overall response rate. In 2 patients response has not been confirmed in a 2^ndtreatment assessment. Median time to first response was 28 days. The median PFS is 6 months. A higher CSF drug concentration was observed at higher doses of Ibrutinib and at steady state. Continued enrollment is ongoing at 840 mg in an expansion cohort. Molecular testing is ongoing to associate genomic alterations and outcome. Conclusions: Patients with CNS lymphoma tolerate Ibrutinib at 560 and 840mg well. Targeted agents might be an alternative therapeutic approach to be investigated for refractory/recurrent CNS lymphoma patients. Clinical trial information: NCT02315326