title: A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer.
abstract: OBJECTIVE
  The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer.
  
  
  METHODS
  Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m(2) every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity.
  
  
  RESULTS
  Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m(2), 19 at 70 mg/m(2), and 4 at 75 mg/m(2)) including dose expansion at 70 mg/m(2). The maximum tolerated dose of docetaxel was 70 to 75 mg/m(2). Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy.
  
  
  CONCLUSIONS
  The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m(2). Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.
authors.affiliation: Duke Prostate Center, 2424 Erwin Road, Durham, NC 27705, USA. andrew.armstrong@duke.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.forename: Patricia
authors.initials: P
authors.lastname: Creel
authors.forename: James
authors.initials: J
authors.lastname: Turnbull
authors.forename: Cassandra
authors.initials: C
authors.lastname: Moore
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Jaffe
authors.forename: Sherri
authors.initials: S
authors.lastname: Haley
authors.forename: William
authors.initials: W
authors.lastname: Petros
authors.forename: Sarah
authors.initials: S
authors.lastname: Yenser
authors.forename: Jon P
authors.initials: JP
authors.lastname: Gockerman
authors.forename: Darryl
authors.initials: D
authors.lastname: Sleep
authors.forename: Herbert
authors.initials: H
authors.lastname: Hurwitz
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077868:Atrasentan; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011759:Pyrrolidines / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D011759:Pyrrolidines; D043823:Taxoids; D000077143:Docetaxel; D000077868:Atrasentan