Phase I Study of Single Agent Ibrutinib in Recurrent/Refractory Primary and Secondary CNS Lymphoma

Abstract

BACKGROUNDPrimary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Standard treatment of PCNSL may include radiation, methotrexate-based therapy, and anti-CD20 antibody therapy (rituximab) and is associated with substantial morbidity and treatment recurrence. Outcome and treatment options for patients with recurrent/refractory disease are poor. There is only limited use of targeted agents in this patient population. Ibrutinib has shown promising clinical response in some B-cell malignancies. This phase I trial investigates the maximal tolerated dose of ibrutinib in patients with recurrent/refractory PCNSL and secondary CNS lymphoma (SCNSL). METHODSEligible patients had a recurrent or refractory 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 or not requiring any active treatment. RESULTSThree patients have been enrolled at dose level 1 (560 mg daily) and one patient at dose level 2 (840mg daily) of whom three were women with a median age of 70 years (range 21-80). Three had recurrent PCNSL and 1 recurrent SCNSL. Two patients presented with parenchymal and two with leptomeningeal relapse. Treatment was generally well tolerated. There was one drug-related grade 4 toxicity (neutropenia) that resolved after the drug was held for 4 days. No drug related grade 3 toxicities have been observed to date. Most common grade 2 toxicities were decreased neutrophil count and hyperglycemia. All patients continue on study at a median follow up of 87 days. Three out of four patient were evaluated for response so far. There were two responses: one complete (in the CSF) and one partial, both in recurrent/refractory PCNSL as well as one stable disease in the patient with recurrent SCNSL. The patient with partial response had failed multiple prior treatment regimens including methotrexate-based chemotherapy, radiation, and rituximab/temozolomide. Serum and CSF pharmacokinetic analysis is initiated. Dose level 2 (840mg) is accruing. CONCLUSIONPatients with CNS lymphoma tolerate Ibrutinib at 560 and 840mg well. Dose escalation will continue. Targeted agents might be an alternative therapeutic approach to be investigated for refractory/recurrent CNS lymphoma patients. DisclosuresNo relevant conflicts of interest to declare.