A phase I dose-escalation study of SR271425, an intravenously dosed thioxanthone analog, administered weekly in patients with refractory solid tumors

Objectives: The thioxanthone analog, SR271425, is a novel cytotoxic DNA-interacting agent with broad antitumor activity in preclinical models. The objectives of this phase I study were to determine the dose-limiting toxicities, maximum tolerated dose, recommended phase II dose, pharmacokinetic profile, and trend for efficacy in patients with advanced cancer. Methods: SR271425 was administered intravenously over 1-hour, weekly for 2 weeks, followed by 1 week rest. Because of C_max-related corrected QT (QT_c) prolongation in preclinical testing of SR271425, all patients underwent an extensive pretreatment cardiac assessment. Results: Eighteen patients received SR271425 at 5 dose levels ranging from 64 to 675 mg/m²/wk. No dose-limiting toxicities were identified. In all tested dose-levels, Grade 3 adverse events were observed in 10/18 patients (55.6%) and Grade 4 in 4/18 patients (22.2%). QT_c prolongation was reported at the 3 highest dose levels but did not exceed Grade 2. Six deaths occurred during the study, 5 of them because of disease progression and 1 because of disease related bowel perforation. SR271425 exposure increased in a near dose-proportional manner. The mean terminal plasma half-life of SR271425 was 6 hours and there was no drug accumulation after repeated dosing. Stable disease was the best outcome observed (5 patients). Conclusions: SR271425 was administered safely at doses up to 675 mg/ m²/wk on a 2-week on, 1-week off schedule. No dose-limiting toxicities were observed. Grade 2 QT_c prolongation was observed at the highest dose levels. Maximum tolerated dose was not reached because of early termination of the SR271425 program by the sponsor.