Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer

Purpose: To determine the maximum-tolerated dose (MTD) and toxicity of PSC 833 infusion administered with to etoposide for 5 days in patients with cancer, and to determine the effect of PSC 833 on etoposide pharmacokinetics. Patients and Methods: Thirty-five patients were entered onto the study, one of whom was ineligible. Etoposide was delivered from day 1 as a 5-hour infusion over 5 consecutive days at a dose of 75 to 100 mg/m(2)/d. PSC 833 was administered from day 2 as a 5-hour loading dose and as a 5-day continuous infusion, Doses were escalated from 1 to 2 mg/kg (loading dose) and 1 to 15 mg/kg/d (continuous infusion). Results: Thirty-four patients were treated with 53 cycles of PSC 833 and etoposide. Steady-state blood PSC 833 levels more than 1,000 ng/mL were achieved in all patients treated at PSC 833 doses greater than or equal to 6.6 mg/kg/d by continuous infusion, Myelosuppression was the most common toxicity. The major dose-related toxicity of PSC 833 was reversible hyperbilirubinemia, which occurred in 83% of cycles. The dose-limiting toxicity of PSC 833 was severe ataxia, which occurred in two of nine patients treated at 12 mg/kg/d and in both of the single patients treated at 13.5 and 15 mg/kg/d. PSC 833 concentrations more than 2,000 ng/mL resulted in an increase in etoposide area under the curve (AUG) of 89%, a decrease in etoposide clearance (Cl) of 45%, a decrease in volume of steady-state distribution (Vss) of 41%, and on insignificant increase in alpha half-life (t(1/2 alpha)) and significant increase of beta half-life (t(1/2 beta)) Of 19% and 77%, respectively. Conclusion: PSC 833 con be administered in combination with etoposide with acceptable toxicity. The recommended continuous infusion dose of PSC 833 for this schedule is 10 mg/kg/d over 5 days, PSC 833 results in an increase in etoposide exposure and etoposide doses should be reduced in patients receiving PSC 833. (C) 1996 by American Society of Clinical Oncology.