Phase I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule

Purpose: SR233377 (WIN33377) is a novel I-aminomethyl thioxanthone derivative with promising preclinical activity against solid tumors at doses substantially below the MTD. We performed a phase I trial to determine a suitable phase II dose of SR233377 when administered at a 2-h intravenous infusion for five consecutive days. Methods, A group of 25 patients with a range of solid turner diagnoses and good performance status received SR233377 at eight dose levels ranging from 4.8 mg/m(2) per day to 74.7 mg/m2 per day. Cycles were repeated every 35 days and patients were evaluated for response following two cycles of treatment. Doses were escalated in cohorts of three using a modified Fibonacci scheme. Pharmacokinetic sampling was performed during the first cycle in all patients. Results: Toxicities of SR233377 on this schedule included neutropenia, fever, nausea, and dyspnea but all were mild and not dose-limiting. Asymptomatic prolongation of the corrected QT (QTc) interval during infusion in all patients monitored at the 74.7 mg/m(2) dose level prompted closure of the study. QT lengthening correlated with increasing plasma concentrations of SR233377. SR233377 C-max values increased linearly with dose, but substantial interpatient variability in SR233377 AUG, clearance, and half-life was noted. There was no evidence of drug accumulation when day 1 and day 5 AUC and C-max values were compared. Seven patients displayed tumor growth inhibition lasting for 4 months or more. Conclusions: We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias, Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted.