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

A. Craig Lockhart, Emiliano Calvo, Anthony W. Tolcher, Eric K. Rowinsky, Gareth Shackleton, J. Gilmour Morrison, Rezvan Rafi, Wendy VerMeulen, Mace L. Rothenberg

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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 Cmax-related corrected QT (QTc) 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%). QTc 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 QTc 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.

Original languageEnglish (US)
Pages (from-to)9-14
Number of pages6
JournalAmerican Journal of Clinical Oncology: Cancer Clinical Trials
Volume32
Issue number1
DOIs
StatePublished - Feb 1 2009
Externally publishedYes

Keywords

  • Clinical trial
  • Phase I
  • Prolongation
  • Qt
  • SR271425
  • Thioxanthone

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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