title: A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor.
abstract: OBJECTIVE
  ZD9331 is a novel, direct-acting antifolate cytotoxic that does not require polyglutamation for activity, and is a specific thymidylate synthase inhibitor. This Phase I trial aimed to determine the maximum tolerated dose of ZD9331, given as a 30-min i.v. infusion on days 1 and 8 of a 21-day cycle. Pharmacokinetic parameters and tumor response were also assessed.
  
  
  METHODS
  A total of 71 patients, with a range of solid malignancies and refractory to standard therapies (44% had received > or =3 prior chemotherapy regimens), were treated. The most common malignancies were colorectal cancer (35% of patients) and ovarian cancer (31%). ZD9331 was escalated from 4.8 mg/m(2)/day.
  
  
  RESULTS
  Dose-limiting toxicity occurred at 162.5 mg/m(2) ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting > or =7 days, and grade 3 nonhematologic toxicity. Plasma clearance of ZD9331 was slow and dose-dependent; however, ZD9331 pharmacokinetics were nonlinear. Pharmacodynamics of ZD9331 were determined by measurement of plasma deoxyuridine, which increased at all of the dose levels; dose-related increases in plasma deoxyuridine were significant (P = 0.003) on day 5. Stable disease was observed in 37% of patients; 23% of ovarian cancer patients had a > or =50% reduction in CA125 levels.
  
  
  CONCLUSIONS
  The maximum tolerated dose of this schedule was 130 mg/m(2). The toxicity profile at this dose was acceptable, with 7 of 28 patients treated developing grade 3/4 neutropenia and thrombocytopenia, 2 grade 4 diarrhea, and 2 grade 3/4 rash. This schedule was convenient and demonstrated activity in extensively pretreated patients; therefore, this is the recommended dose for study in Phase II trials.
authors.affiliation: University of Newcastle upon Tyne, Newcastle NE4 6BE, United Kingdom. e.r.plummer@ncl.ac.uk
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rees
authors.forename: Andrew
authors.initials: A
authors.lastname: Hughes
authors.forename: Philip
authors.initials: P
authors.lastname: Beale
authors.forename: Martin
authors.initials: M
authors.lastname: Highley
authors.forename: Jose
authors.initials: J
authors.lastname: Trigo
authors.forename: Sathyarathnarn
authors.initials: S
authors.lastname: Gokul
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.forename: Hilary
authors.initials: H
authors.lastname: Calvert
authors.forename: Ann
authors.initials: A
authors.lastname: Jackman
authors.forename: Fraser
authors.initials: F
authors.lastname: Mitchell
authors.forename: Robert
authors.initials: R
authors.lastname: Smith
authors.forename: Edwin
authors.initials: E
authors.lastname: Douglass
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C094299:ZD 9331; D014867:Water; D013940:Thymidylate Synthase