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

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/m(2) paclitaxel over 3 h starting 4 h after initiation of a 24-h continuous i.v. infusion of 120 mg/m(2)/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 10(9) 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 microg x h/ml) and clearance (5.1 +/- 1.3 liters/h/m(2)) during the first treatment cycle were comparable with standard 175 mg/m(2) 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 8 Issue 3 Pg. 670-8 (Mar 2002) ISSN: 1078-0432 [Print] United States
• PMID: 11895894 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Evaluation Study, 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 (metabolism)
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, secondary)
• Disease Progression
• Disease-Free Survival
• Drug Administration Schedule
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Female
• Humans
• Male
• Middle Aged
• Multidrug Resistance-Associated Proteins (metabolism)
• Neoplasm Recurrence, Local (drug therapy, prevention & control)
• Paclitaxel (administration & dosage, adverse effects, pharmacokinetics)
• Piperidines (administration & dosage, adverse effects, pharmacokinetics)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics)
• Safety
• Time Factors
• Tissue Distribution
• Treatment Outcome