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A Phase II Study of the MDR Inhibitor Biricodar (INCEL, VX-710) and Paclitaxel in Women with Advanced Ovarian Cancer Refractory to Paclitaxel Therapy

2002; Elsevier BV; Volume: 86; Issue: 3 Linguagem: Inglês

10.1006/gyno.2002.6762

1095-6859

Michael V. Seiden, Kenneth D. Swenerton, Ursula A. Matulonis, Susan Campos, Peter G. Rose, Gerald Batist, Ene Ette, Varun Garg, A. Fuller, Matthew W. Harding, Danielle Charpentier,

Ovarian cancer diagnosis and treatment

Abstract Purpose. Incel (biricodar, VX-710) 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 advanced ovarian cancer 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 disease within 4 months of prior paclitaxel therapy. Patients received 80 mg/m 2 paclitaxel over 3 h starting 4 h after initiation of a 24-h continuous intravenous infusion of 120 mg/m 2 /h VX-710. Cycles were repeated every 3 weeks. Results. Fifty patients received treatment and 45 were evaluable for response. VX-710 + paclitaxel therapy was generally well tolerated. Myelosuppression was the principal toxicity, with a median Cycle 1 nadir absolute neutrophil count of 0.27 × 10 9 cells/L and a 47% overall incidence of Grade 4 neutropenia. Mild to moderate peripheral neuritis or neuropathy was the primary nonhematologic toxicity, affecting 62% of patients. Other nonhematologic toxicities were generally mild to moderate and reversible. Paclitaxel area under the concentration-versus-time curve (AUC) (16 ± 5.3 μg × h/mL) during the first treatment cycle was comparable to standard 175 mg/m 2 paclitaxel administered over 3 h. Of the 3 patients who achieved partial responses, 2 had progressed during prior paclitaxel therapy. Twelve patients maintained stable disease and 14/45 (31%) of patients had CA-125 reductions of 50–90% for up to 24 weeks. The median time-to-disease progression was 10 weeks for the intent-to-treat population and 20.7 weeks for the CA-125 responders. Conclusions. The results suggest that VX-710 with paclitaxel has modest activity in paclitaxel-resistant ovarian cancer. Further research is warranted in less heavily treated patients.