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

D Toppmeyer, AD Seidman, M Pollak, C Russell… - Clinical Cancer …, 2002 - AACR
D Toppmeyer, AD Seidman, M Pollak, C Russell, K Tkaczuk, S Verma, B Overmoyer, V Garg…
Clinical Cancer Research, 2002AACR
Abstract Purpose: VX-710 (biricodar, Incel) restores drug sensitivity to P-glycoprotein (MDR
1) 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 …
Abstract
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 initiation 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.
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