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

BACKGROUND:  Primary 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).

METHODS:   Eligible 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.

RESULTS:  Three 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.

CONCLUSION:  Patients 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.