A phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (valspodar)

BACKGROUND. PSC 833 is a second- generation P-glycoprotein (Pgp). antagonis t developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastin e administered as a 5-day continuous infusion. METHODS. Seventy-nine patients with advanced malignant disease were enrolle d in the trial and treated with escalating doses of PSC 833. Pharmacokineti c interactions between PSC 833 and vinblastine were anticipated. Accordingl y, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS. The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally ever y 12 hours for 8 days for the liquid formulation in combination with 0.9 mg /m(2) per day vinblastine as a continuous intravenous infusion (CM for 5 da ys; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formu lation in combination with 0.6 mg/m(2) per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for t he combination, constipation, fever. and neutropenia. Increased oral bioava ilability and increased peak and trough concentrations were observed with t he microemulsion formulation. Significant interpatient variability in pharm acokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp ant agonism. Among 43 evaluable patients with clear cell carcinoma of the kidne y, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS. PSC 833 in combination with vinblastine can be administered sa fely to patients provided the vinblastine dose is adjusted for pharmacokine tic interactions. The high interpatient variability is a significant confou nding factor. Surrogate studies with CD56 positive cells suggest that Pgp i nhibition in the clinical setting is achievable, Improved methods for predi cting pharmacokinetic interactions should improve future studies. (C) 2001 American Cancer Society.