title: Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  This two-part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer.
  
  
  METHODS
  Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Patients received once-daily oral zibotentan 10 mg (initial cohort) or 15 mg in combination with docetaxel 75 mg/m(2) (administered on day 1 of each 21-day cycle) for up to 10 cycles. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized 2:1 to receive zibotentan (at the highest tolerated dose identified in part A) plus docetaxel or placebo plus docetaxel.
  
  
  RESULTS
  Six patients were enrolled in part A (n  = 3, zibotentan 10 mg; n = 3, zibotentan 15 mg). No dose-limiting toxicity was observed, thus zibotentan 15 mg in combination with docetaxel was evaluated in part B (n = 20, zibotentan plus docetaxel; n = 11, placebo plus docetaxel). CTCAE grade ≥3, most commonly neutropenia or leucopenia, were reported in 10 (50%) and nine (82%) patients in the zibotentan and placebo groups, respectively. One (17%) patient receiving placebo achieved complete response, two (22%) patients receiving zibotentan achieved partial response and stable disease occurred in six (67%) and three (50%) patients receiving zibotentan and placebo, respectively.
  
  
  CONCLUSIONS
  The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development.
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA. donald.trump@roswellpark.org
authors.forename: Donald L
authors.initials: DL
authors.lastname: Trump
authors.forename: Heather
authors.initials: H
authors.lastname: Payne
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Joe
authors.initials: J
authors.lastname: Stephenson
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Faith
authors.initials: F
authors.lastname: Nathan
authors.forename: Maria
authors.initials: M
authors.lastname: Taboada
authors.forename: Thomas
authors.initials: T
authors.lastname: Morris
authors.forename: Andreas
authors.initials: A
authors.lastname: Hubner
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000503:physiopathology / Q000556:secondary*; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001859:Bone Neoplasms / Q000188:drug therapy / Q000503:physiopathology / Q000556:secondary; D015331:Cohort Studies; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D009919:Orchiectomy; D010146:Pain / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000601:surgery; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D043823:Taxoids; C511404:ZD4054; D000077143:Docetaxel