PHASE-I AND PHARMACOKINETIC STUDY OF PACLITAXEL IN COMBINATION WITH BIRICODAR, A NOVEL AGENT THAT REVERSES MULTIDRUG-RESISTANCE CONFERRED BY OVEREXPRESSION OF BOTH MDR1 AND MRP

Purpose: To evaluate the feasibility of administering biricodar (VX-71 0; Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that mo dulates multidrug resistance (MDR) conferred by overexpression of both the multidrug resistance gene product (MDR1) P-glycoprotein and the M DR associated protein (MRP) in vitro, in combination with paclitaxel. The study also sought to determine the maximum-tolerated dose (MTD) of paclitaxel that could be administered with biologically relevant conc entrations of VX-710 and characterize the toxicologic and pharmacologi c profiles of the VX-710/paclitaxel regimen. Patients and Methods: Pat ients with solid malignancies were initially treated with VX-710 as a 24-hour infusion at doses that ranged from 10 to 120 mg/m(2) per hour After a 5-day washout period, patients were re-treated with VX-710 on an identical dose schedule followed 8 hours later by paclitaxel as a 3 -hour infusion at doses that ranged from 20 to 80 mg/m(2). The pharmac okinetics of both VX-710 and paclitaxel were studied during treatment with VX-710 alone and VX-710 and paclitaxel. Thereafter, patients rece ived VX-710 and paclitaxel every 3 weeks. Results: VX-710 alone produc ed minimal toxicity. The toxicologic profile of the VX-710/paclitaxel regimen was similar to that reported with paclitaxel alone; neutropeni a that was noncumulative was the principal dose-limiting toxicity (DLT ). The MTD levels of VX-710/paclitaxel were 120 mg/m(2) per hour and 6 0 mg/m(2), respectively, in heavily pretreated patients and 120/60 to 80 mg/m(2) per hour in less heavily pretreated patients. At these dose levels, VX-710 steady state plasma concentrations (C-55) ranged from 2.68 to 4.89 mu g/mL, which exceeded optimal VX-710 concentrations req uired for MDR reversal in vitro. The pharmacokinetics of VX-710 were d ose independent and not influenced by paclitaxel. In contrast, VX-710 reduced paclitaxel clearance. At the two highest dose levels, which co nsisted of VX-710 120 mg/m(2) per hour and paclitaxel 60 and 80 mg/m(2 ), pertinent pharacokinetic determinants of paclitaxel effect were sim ilar to those achieved with paclitaxel as a 3-hour infusion at doses o f 135 and 175 mg/m(2), respectively. Conclusion: VX-710 alone is assoc iated with minimal toxicity. In combination with paclitaxel, biologica lly relevant VX-710 plasma concentrations are achieved and sustained f or 24 hours, which simulates optimal pharmacologic conditions required for MDR reversal in vitro. The acceptable toxicity profile of the VX- 710/paclitaxel combination and the demonstration that optimal pharmaco logic conditions for MDR reversal are achievable support a rationale f or further trials of VX-710/paclitaxel in patients with malignancies t hat are associated with de nova or acquired resistance to paclitaxel c aused by overexpression of Mop I and/or MRP. J Clin Oncol 16:2964-2976 . (C) 1998 by American Society of Clinical Oncology.