Lisavanbulin (BAL101553), a novel microtubule inhibitor, plus radiation in patients with newly diagnosed, MGMT promoter unmethylated glioblastoma.

Abstract

Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models. This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Dose escalation followed a modified 3 + 3 design. Secondary objectives included estimation of OS and PFS and pharmacokinetic analysis. Twenty-six patients with uGBM (median age, 63 years, 42.3% male, 61.5% with gross total resection, median Karnofsky performance status 80) were enrolled; 2 tumors had an IDH1 mutation. Predefined dose levels of Lisavanbulin, administered daily concomitantly with RT, were: 4mg (5 pts), 6mg (5 pts), 8mg (7 pts), 12mg (5 pts), and 15mg (4 pts). The initial starting dose was 8mg. Due to grade 4 aseptic meningoencephalitis in the first patient, the dose was decreased to 4mg. Dose escalation resumed and continued to 15mg with dose-limiting toxicities of grade 2 confusion and memory impairment observed at 12mg. Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15mg. Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15mg daily.