A phase II study of the MDR inhibitor biricodar (INCEL, VX-710) and paclitaxel in women with advanced ovarian cancer refractory to paclitaxel therapy.

Abstract

PURPOSE:

Incel (biricodar, VX-710) 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 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 x 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 microg x 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.

• Authors: Michael V Seiden, Kenneth D Swenerton, Ursula Matulonis, Susan Campos, Peter Rose, Gerald Batist, Ene Ette, Varun Garg, Arlan Fuller, Matthew W Harding, Danielle Charpentier
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 86 Issue 3 Pg. 302-10 (Sep 2002) ISSN: 0090-8258 [Print] United States
• PMID: 12217752 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Multidrug Resistance-Associated Proteins
• Piperidines
• Pyridines
• biricodar
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Female
• Humans
• Middle Aged
• Multidrug Resistance-Associated Proteins (antagonists & inhibitors)
• Neoplasm Recurrence, Local (drug therapy)
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Paclitaxel (administration & dosage, adverse effects, pharmacokinetics)
• Piperidines (administration & dosage, adverse effects, pharmacokinetics)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics)