title: Phase I trial of the antifolate ZD9331 in combination with cisplatin in patients with refractory solid malignancies.
abstract: OBJECTIVE
  To determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of ZD9331 in combination with cisplatin in patients with refractory solid tumors and to describe any preliminary antitumor activity associated with this regimen.
  
  
  METHODS
  Patients received combination therapy with ZD9331 as a 30-min infusion on days 1 and 8 of a 21-day cycle at doses of 100 or 130 mg/m(2), followed by cisplatin at 50 or 75 mg/m(2) as a 30- to 60-min infusion on day 1 only.
  
  
  RESULTS
  A total of 16 patients received 59 cycles of ZD9331 and cisplatin. Patients were enrolled at three dose levels: ZD9331/cisplatin 100/50 ( n=3), 130/50 ( n=9), 130/75 ( n=4). DLTs at 130/75 included thrombocytopenia, neutropenia, fatigue, nausea, vomiting and stomatitis. Among 15 evaluable patients, 2 showed a partial response (patients with mesothelioma and head and neck cancer) and 6 showed stable disease (for a median of 5.5 cycles).
  
  
  CONCLUSIONS
  ZD9331 in combination with cisplatin was well tolerated at a dose of 130/50 mg/m(2) after establishing the principal DLTs of neutropenia and thrombocytopenia. The combination shows evidence of antitumor activity in a pretreated population.
authors.affiliation: Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Bilenker
authors.forename: James P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Kenneth
authors.initials: K
authors.lastname: Algazy
authors.forename: Kathy
authors.initials: K
authors.lastname: McLaughlin
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Haller
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Giantonio
authors.forename: M
authors.initials: M
authors.lastname: Koehler
authors.forename: J E
authors.initials: JE
authors.lastname: Garcia-Vargas
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D005493:Folic Acid Antagonists; D011799:Quinazolines; C094299:ZD 9331; D002945:Cisplatin