title: Phase I study of docetaxel in combination with the P-glycoprotein inhibitor, zosuquidar, in resistant malignancies.
abstract: OBJECTIVE
  To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of docetaxel infused over 1 hour when given in combination with oral zosuquidar to patients with resistant solid tumors.
  
  
  METHODS
  In cycle 1, patients received docetaxel alone. In subsequent cycles, zosuquidar was administered with docetaxel, which was escalated from 75 to 100 mg/m2. Zosuquidar was escalated from 100 to 300 mg/m2 every 8 hours on days 1 to 3 for a total of 7 doses, or from 400 to 500 mg every 12 hours for 2 doses administered 2 hours before docetaxel. The pharmacokinetics of docetaxel with and without zosuquidar administration were obtained.
  
  
  RESULTS
  Thirty-six of 41 patients completed at least one cycle of docetaxel and zosuquidar. The maximum tolerated dose was docetaxel 100 mg/m2 and zosuquidar 500 mg every 12 hours for 2 doses. The most common toxicity was neutropenia. In 35 patients, zosuquidar produced minimal increases in the docetaxel peak plasma concentrations and area under the curve. Dosing over 3 days with zosuquidar (7 doses) did not show benefit over the 1-day dosing. Of the 36 patients, one patient had a partial response, and 14 patients had disease stabilization.
  
  
  CONCLUSIONS
  Docetaxel at 75 or 100 mg/m2 and zosuquidar 500 mg 2 hours before docetaxel and 12 hours later is well tolerated. Zosuquidar minimally alters the pharmacokinetics of docetaxel, allowing full dose docetaxel to be given with this P-glycoprotein modulator. A Phase II study with this combination in advanced breast carcinoma is underway.
authors.affiliation: Department of Medicine, Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA. fracasso@wustl.edu
authors.forename: Paula M
authors.initials: PM
authors.lastname: Fracasso
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Goldstein
authors.forename: Dinesh P
authors.initials: DP
authors.lastname: de Alwis
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Arquette
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Goodner
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Wright
authors.forename: Carole L
authors.initials: CL
authors.lastname: Fears
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gazak
authors.forename: Valerie A M
authors.initials: VA
authors.lastname: Andre
authors.forename: Michael F
authors.initials: MF
authors.lastname: Burgess
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Slapak
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D003986:Dibenzocycloheptenes / Q000008:administration & dosage*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000473:pathology*; D011804:Quinolines / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D011804:Quinolines; D043823:Taxoids; D000077143:Docetaxel; C095179:zosuquidar trihydrochloride