ATNT-11A PHASE I PHARMACODYNAMIC STUDY OF DISULFIRAM AND TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA AFTER RADIATION THERAPY AND CONCURRENT TEMOZOLOMIDE

Abstract

BACKGROUND: Preclinical studies have shown that disulfiram (DSF) has promising activity against glioblastoma (GBM) and is synergistic with temozolomide (TMZ). These studies have also suggested that the mechanism is related to the inhibition of proteasomal activity. METHODS: We conducted an open-label, dose-escalation pharmacodynamic study to combine DSF with maintenance TMZ for newly diagnosed GBM after radiation therapy (RT) and concurrent TMZ. The pharmacodynamic effect of DSF on proteasome inhibition was evaluated on peripheral bloods cells, with complete inhibition defined as at least 5 patients with 95% proteasome inhibition in a given cohort. Dose escalation occurred if both incomplete proteasome inhibition and less than 2 dose-limiting toxicities (2 DLTs) were observed in cohort 1. Cohort 1 and 2 received DSF 500 mg and 1000 mg daily, respectively. The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which at least 2 patients of a cohort experienced DLT during the first month of disulfiram. The primary endpoint was to assess the magnitude of proteasome inhibition by DSF. The secondary endpoint was to determine the MTD of DSF with TMZ. RESULTS: Seven patients were enrolled in cohort 1 (median duration of DSF: 55 days, range: 24-165), and five patients in cohort 2 (median: 15 days, range: 15-33). No DLT was observed in cohort 1, but 4 of 5 patients in cohort 2 stopped DSF during the first month due to toxicity, including 3 DLTs. Incomplete proteasome inhibition was observed at 500 mg level. Six of 7 patients in cohort 1 had progressed, with a median time to progression of 3.6 months (range: 1.6-6.8) from the start of DSF or 6.2 months (range: 4.2-9.5) from the start of RT. CONCLUSIONS: The MTD of DSF with TMZ is 500 mg daily, which is associated with incomplete proteasome inhibition.