A phase I dose-escalation study of weekly multiple dose intravenously administered SR271425 in patients with refractory solid tumors

Abstract

3095 Background: The thioxanthone analog, SR271425, is a novel cytotoxic DNA-interacting agent with a broad spectrum of antitumor activity in preclinical murine tumor models. This clinical trial aims to determine tolerability and toxicities of SR271425 as a 1-hour single intravenous dose repeated weekly for 2 weeks followed by 1 week rest, to determine the maximum tolerated dose (MTD), recommended phase II dose (RPIID), and to assess its pharmacokinetic profile. Methods: A modified Fibonacci dose escalation design is being used. A single intravenous dose of SR271425 is administered over 1-hour weekly for 2 weeks, followed by 1 week rest, in a variety of refractory solid tumors. Of note, in the rabbit model, QTc prolongation, related to Cmax, has been reported at doses >660mg/m2. Therefore, all patients are undergoing cardiology assessment with serial ECGs, which are assessed by a central reviewer. Results: To date, 17 patients have been treated at 5 dose levels (ranges, 64–675 mg/m2/week). The mean age is 53 (range 24 -74 years) and ECOG performance status is 0–2. Grade 1–2 toxicities including QTc prolongation, nausea/vomiting/ constipation, and fatigue have been observed. The pharmacokinetics of SR271425 following weekly dosing were consistent with that observed previously in a single dose ascending study with SR271425. Both Cmax and AUC (day 1) increased in a dose dependent manner. As would be predicted from the drugs short half-life (6.7 h), no systemic accumulation was observed as assessed by Cmax and C6h values on Day 1 versus Day 8. Stable disease has been observed in 3 patients. Conclusions: Preliminary data on this ongoing study suggests that SR271425 administered at split, weekly doses will likely allow greater cumulative exposure without significant toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo Research