Phase I dose-finding and pharmacokinetic study of paclitaxel and carboplatin with oral valspodar in patients with advanced solid tumors

Purpose: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxici ties (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine a nalog valspodar (PSC 833), an inhibitor of P-glycoprotein function. Patients and methods: Fifty-eight patients were treated with escalating dos es of paclitaxel ranging from 54 to 94.5 mg/m(2) and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg.mi n/ml, every 21 days. The dose of valspodar was fixed at 5 mg/kg every d hou rs for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated and (2) chemotherapy-naive patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg.m in/ml. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. Results: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic tran saminase elevations were DLTs, In previously treated patients, no DLTs occu rred at the first dose level (paclitaxel 54 mg/m2 and carboplatin AUC 6 mg. min/ml). However, one of 1 2, two of six, two of four, four of 1 1,and two of five patients experienced DLTs at doses of paclitaxel (mg/m(2))/carbopla tin AUC (mg.min/mL) of 67.5/6 81/6, 94.5/6, 67.5/7.5, and 67.5/9, respectiv ely. In chemotherapy-naive patients, one of 17 developed DLT at paclitaxel 81 mg/m(2) and carboplatin AUC 6 mg/ ml min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was greater than or equal to 0.05 mu m ol/L, ranging from 16.6 +/- 6.7 hours to 41.5 +/- 9.8 hours for paclitaxel doses of 54.5 mg/m(2) to 94.5 mg/ m(2), respectively. Conclusion: The recommended phase II dose in chemotherapy-naive patients is paclitaxel 81 mg/m(2), carboplatin AUC 6 mg min/ml, and valspodar 5 mg/kg every d hours. In previously treated patients, the recommended phase II dos e is paclitaxel 67.5 mg/m(2), carboplatin AUC d mg min/ml, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study. (C) 2000 by American So ciety of Clinical Oncology.