Phase I pharmacokinetic study of the novel antitumor agent SR233377

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor s electivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurolog ical toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I c linical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m(2) (one-tenth the mo use LD10), Escalations continued to 445 mg/m(2) (six escalations), where do se-limiting toxicity was observed. At this dose, acute ventricular arrhythm ias, including one patient with torsades de pointes and transient cardiac a rrest, occurred. Because this toxicity might have been related to the plasm a peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QT(C)) over the pretreatment levels resulted. Because prolonged QT, is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stop ped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar a ntitumor effects that is devoid of cardiac toxic effects.