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

Deborah Toppmeyer, Andrew D. Seidman, Michael Pollak, Christy Russell, Katherine Tkaczuk, Shailendra Verma, Beth Overmoyer, Varun Garg, Ene Ette, Matthew W. Harding, George D. Demetri

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74 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)670-678
Number of pages9
JournalClinical Cancer Research
Volume8
Issue number3
StatePublished - Jan 1 2002

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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