Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833

Purpose: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) an tagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclita xel, administered as a 96-hour continuous infusion. Patients and Methods: Fifty patients with advanced cancer were enrolled ont o the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion, Paclitaxel dose reductions we re planned because of the pharmacokinetic interactions known to occur with PSC 833. Results: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 d ays without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutrope nia. Statistical analysis of cohorts revealed similar mean steady-state con centrations (C-pss) and areas under the concentration-versus-time curve (AU Cs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received ct paclitaxel dose of 35 mg/m(2)/ d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surro gate assay using CD56+ cells suggested inhibition of Pgp was complete or ne arly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occ urred in five of 10 patients with ovarian carcinoma. Conclusion: PSC 833 in combination with paclitaxel can be administered safe ly to patients provided the paclitaxel dose is reduced to compensate for th e pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokin etics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharm acokinetic interaction. Future development of combinations such as this sho uld include strategies to predict pharmacokinetics of the chemotherapeutic agent, This in turn will facilitate dosing to achieve comparable CPss and A UCs. (C) 2001 by American Society of Clinical Oncology.