This multidrug resistant (MDR) phenotype due to the overexpression of MDR1/Pgp is a documentated mechanism of drug resistance in patients with multiple myeloma. Several currently available compounds such as verapamil and Cyclosporin A can modulate MDR: however, clinical studies have demonstrated substantial toxicity and limited efficacity. PSC 833 is a non-immunosuppressive, non-nephrotoxic derivative of Cyclosporin D, specifically selected for its ability to modulate Pgp and reverse MDR. Thirty-one patients, 28 with relapsed myeloma and 3 with relapsed, low- grade non-Hodgkin's lymphoma were enrolled in a Phase I trial of PSC 833 in combination with Vincristine, Daxorubicin, and Dexamethasone (VAD). PSC 833 was administered orally, either as a soft-gelatin capsule or an oral solution, according to 5 different dosing schedules. Thirteen patients were treated at the final recommended dose (FRD) of PSC 833 plus VAD. THe FRD of PSC 833 oral solution was 4 mg/kg qid. FRD for 4 days of vincristine was reduced from the standard dose of 0.4 mg/day to 0.2 mg/day, and the FRD of doxorubicin was reduced form the standard of 9 mg/m2/day to 7 mg/m2/day. Significant myelosuppression was observed at all dosing levels (77% of patients), with grades 3 or 4 granulocytopenia observed in 38% of patients treated at FRD. Four of 31 patients had neutropenia fevers, but there were no toxic deaths. Unique non-hematologic toxicities, not usually associated with VAD, were transient staxia (48%) with 8% grade 3 and no grade 4 staxia noted at FRD; and hyperbilirubinemia (35%) with 15% grade 3 and 8% grade 4 bilirubin elevations at FRD. Pharmacokinetic analysis of whole blood concentrations of PSC 833 showed that 12 of 13 patients (92%) in 28 of 29 cycles (97%) receiving the FRD of PSC 833 (4mg/kg/qid) achieved adequate concentrations of PSC 833 (>1000 ng/ml) known to reverse MDR in vitro. Of the 26 myeloma patients evaluable for response, 5 patients had a partial response and 3 patients had a minor response. Studies to determine the effects of PSC 833 on doxorubicin pharmacokinetics are currently being analyzed. Phase II and III studies of PSC 833 plus VAD in patients with myeloma will soon be underway using the doses determined from this Phase I study.
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