A phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors

Abstract

Purpose: Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1α and vascular endothelial growth factor. Objectives of this study were to determine safety, tolerability, pharmacodynamics, and pharmacokinetics of PX-12, a small-molecule inhibitor of Trx-1. Experimental Design: Thirty-eight patients with advanced solid tumors received PX-12 at doses of 9 to 300 mg/m2, as a 1- or 3-h i.v. infusion on days 1 to 5, repeated every 3 weeks. Results: At the 300 mg/m2 dose level, one patient experienced a reversible episode of pneumonitis during the first cycle, and a second patient developed pneumonitis after the second cycle. Doses up to 226 mg/m2 were well tolerated, and grade 3/4 events were uncommon (<3% of patients). The limiting factor on this dosing schedule was pungent odor caused by expired drug metabolite, 2-butanethiol. The best response was stable disease in seven patients (126-332 days). Whereas PX-12 was not detectable following the infusion, the Cmax of its inactive metabolite, 2-mercaptoimidazole, increased linearly with dose. PX-12 treatment lowered plasma Trx-1 concentrations in a dose-dependent manner. Conclusions: PX-12, the first Trx-1 inhibitor to enter clinical trials, was tolerated up to a dose of 226 mg/m 2 by a 3-h infusion. Based on pharmacodynamic and pharmacokinetic data, a trial of prolonged infusion schedule of PX-12 has been initiated. © 2007 American Association for Cancer Research.