The primary objective of this phase I dose escalation study was to evaluate the safety, tolerability and to determine the maximum tolerate dose (MTD) of pemetrexed, an anti-folate drug with broader activity than methotrexate, in patients with central nervous system lymphoma (CNSL). Secondary objectives were to assess progression-free survival (PFS), overall survival (OS), and overall response to treatment.

CNSL is a rare and aggressive disease with a high risk of relapse. Despite improvements in the treatments of CNSL, most patients with develop tumor progression, and there is currently no standard salvage treatment for patients with relapsed/refractory CNSL.

Through October 2015, 18 patients with primary or relapsed/refractory CNSL were recruited. Treatment consisted of pemetrexed given every two weeks with a starting dose at 600mg/m², and dose escalation in increments of 300mg/m² to a maximum of 1500mg/m². Each treatment cycle was defined as two weeks, and treatment response was assessed by Magnetic Resonance Imaging every two cycles.

14 patients were evaluable with a median age of 64.6 years. Main adverse events were fatigue (100%), anemia (100%) and neutropenia (85.7%). The MTD was established at 900mg/m². 3/14 patients (21.4%) achieved a complete response, 5/14 patients (35.7%) had a partial response, 2/14 patients (14.3%) had stable disease, and 4/14 patients (28.6%) had progressive disease. PFS at 6 months was 35.7% with a median PFS at 4.2 months. The median OS was 44.5 months. The estimated 1-year, 2-year and 5-year survival rate were 78.6%, 64.3% and 35.7%, respectively.

Pemetrexed exhibits single-agent activity in heavily pre-treated patients with recurrent CNSL, is well tolerated and side effects are manageable. Pemetrexed remains a viable treatment option in this patient population.