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Safety and Efficacy of the Multidrug-Resistance Inhibitor Biricodar (VX-710) with Concurrent Doxorubicin in Patients with Anthracycline-resistant Advanced Soft Tissue Sarcoma¹

London Regional Cancer Centre, London, Ontario, Canada N6A 4L6 [V. H. C. B.]; Tom Baker Cancer Centre, Calgary, Alberta T2N 4N2 Canada [D. M., D. S. E.]; Montreal General Hospital, Montreal, Quebec, H3G 1A4 Canada [I. H.]; Mount Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada [M. B.]; Cross Cancer Institute, Edmonton, Alberta T6G 1Z2 Canada [P. M. V.]; Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139 [E. E., M. W. H.]; and Dana Farber Cancer Institute, Boston, Massachusetts 02115 [A. W., G. D. D.]

Purpose: Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein and multidrug resistance-associated protein-1-expressing cells. This Phase I/II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus doxorubicin in patients with inoperable, locally advanced or metastatic, anthracycline-resistant/refractory, soft tissue sarcoma.

Experimental Design: In Phase I, i.v. bolus doxorubicin at 60, 75, or 67.5 mg/m² was administered 8 h after initiation of a 72-h continuous i.v. (CIV) infusion of VX-710 (120 mg/m²/h) to cohorts of patients to establish a maximum tolerated dose. For efficacy evaluations in Phase II, eligible patients had inoperable, locally advanced or metastatic, anthracycline-resistant/refractory soft tissue sarcoma; 225 mg/m² cumulative prior doxorubicin; and adequate hematological, liver, and kidney function. Cycles were repeated every 3 weeks.

Results: Fourteen patients were enrolled in Phase I. Myelosuppression was the dose-limiting toxicity with 75 and then 67.5 mg/m² doxorubicin, and the maximum tolerated dose was established at 60 mg/m² with VX-710, 120 mg/m²/h, 72-h CIV. VX-710 had no apparent effect on doxorubicin pharmacokinetics. Twenty-nine patients enrolled in Phase II were treated with VX-710, 120 mg/m²/h 72-h CIV, and 60 mg/m² doxorubicin. Among 26 evaluable patients, minimal activity was noted among 11 patients with gastrointestinal stromal tumors (GISTs); however, in 15 patients with anthracycline-resistant sarcomas of other histologies, 2 achieved partial responses and 7 patients had disease stabilization with an overall median progression-free interval of 3.4 months.

Conclusion: Anthracycline resistance in GISTs appears to be independent of P-glycoprotein or multidrug resistance-associated protein-1 resistance mechanisms. However, the combination of VX-710 and doxorubicin resulted in objective responses or disease stabilization in patients with strictly defined anthracycline-refractory non-GIST sarcomas, which warrants further evaluation.

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