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Safety and Efficacy of the Multidrug Resistance Inhibitor Incel (Biricodar; VX-710) in Combination with Paclitaxel for Advanced Breast Cancer Refractory to Paclitaxel

Cancer Institute of New Jersey, New Brunswick, New Jersey 08903 [D. T.]; Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [A. D. S.]; Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2 [M. P.]; USC Norris Cancer Center, Los Angeles, California 90033 [C. R.]; University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland 21201 [K. T.]; Ottawa Regional Cancer Center, Ottawa, Ontario, Canada K1H 8L6 [S. V.]; Cleveland Clinic, Cleveland, Ohio 44195 [B. O.]; Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139 [V. G., E. E., M. W. H.]; and Dana Farber Cancer Institute, Boston, Massachusetts 02115 [G. D. D.]

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 x 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 x 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.

Commentary

Modulating Multidrug Resistance: Can We Target this Therapy?

John R. Murren
Clin. Cancer Res. 2002 8: 633-635. [Full Text] [PDF]

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