title: Safety and efficacy of the multidrug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Toppmeyer
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Seidman
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Christy
authors.initials: C
authors.lastname: Russell
authors.forename: Katherine
authors.initials: K
authors.lastname: Tkaczuk
authors.forename: Shailendra
authors.initials: S
authors.lastname: Verma
authors.forename: Beth
authors.initials: B
authors.lastname: Overmoyer
authors.forename: Varun
authors.initials: V
authors.lastname: Garg
authors.forename: Ene
authors.initials: E
authors.lastname: Ette
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Harding
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000517:prevention & control; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012449:Safety; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; C106077:biricodar