Safety and efficacy of the multidrug resistance inhibitor incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel

Purpose: VX-710 (biricodar, Incel) restores drug sensitivity to P-glycoprotein (MDR1) and multidrug resistance-associated protein (MRP1)-expressing cells. This Phase II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with locally advanced or metastatic breast cancer who were refractory to prior paclitaxel therapy. Experimental Design: Eligible patients had paclitaxel-refractory disease defined as progressive disease after a minimum of two cycles of paclitaxel (weekly or 3-week schedule) or relapsed/progressive disease within 6 months of prior paclitaxel therapy. Patients received 80 mg/m² paclitaxel over 3 h starting 4 h after initiatiion of a 24-h continuous i.v. infusion of 120 mg/m²/h VX-710. Cycles were repeated every 3 weeks. Results: Thirty-seven patients received study treatment and 35 were evaluable for response. VX-710 + paclitaxel therapy was generally well tolerated. Myelosuppression was the principal toxicity, with a median nadir ANC cycle 1 of 0.76 × 10⁹ cells/liter and a 40% overall incidence of Grade 4 neutropenia. Nonhematological side effects (asthenia, paresthesia, headache, myalgia, nausea, and diarrhea) were generally mild to moderate and reversible. Paclitaxel AUC (16.8 ± 5.0 μg × h/ml) and clearance (5.1 ± 1.3 liters/h/m²) during the first treatment cycle were comparable with standard 175 mg/m² paclitaxel administered in a 3-h schedule. Four patients achieved partial responses (three of the four had progressive disease on prior paclitaxel) with a mean response duration of 5.5 months. Conclusions: The 11.4% (4 of 35) objective response rate observed in this study suggests that VX-710 can resensitize a subgroup of paclitaxel-refractory patients to paclitaxel. The safety and pharmacokinetics of the VX-710/pacitaxel regimen support further evaluation in breast cancer patients with initial paclitaxel therapy to prevent emergence of the MDR phenotype in recurrent disease.