title: Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors.
abstract: OBJECTIVE
  A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects.
  
  
  METHODS
  In vitro and in vivo preclinical studies demonstrated increased activity with prolonged nolatrexed exposure. In 32 patients, nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition.
  
  
  RESULTS
  The MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatrexed were predictable and reversible. A partial response that lasted 3 months occurred in a patient with metastatic colorectal cancer. Pharmacokinetics were nonlinear, with the median plasma clearance (CI) decreasing from 151 mL/min/m2 (range, 124 to 211) at 96 mg/m2/d for 5 days to 49 mL/min/m2 (range, 30 to 84) at 768 mg/ m2/d for 5 days. The half-life (t1/2) was 173 minutes (range, 43 to 784) and 18% (range, 9% to 35%) of the dose was excreted unchanged in the urine. Plasma UdR increased, but returned to pretreatment levels after the end of infusion. Hematologic toxicity was significantly related to nolatrexed plasma concentrations and dose.
  
  
  CONCLUSIONS
  Nolatrexed can be safely administered to patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects. The phase II evaluation of nolatrexed is ongoing.
authors.affiliation: Cancer Research Unit, University of Newcastle, Newcastle upon Tyne, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Rafi
authors.forename: A V
authors.initials: AV
authors.lastname: Boddy
authors.forename: J A
authors.initials: JA
authors.lastname: Calvete
authors.forename: G A
authors.initials: GA
authors.lastname: Taylor
authors.forename: D R
authors.initials: DR
authors.lastname: Newell
authors.forename: N P
authors.initials: NP
authors.lastname: Bailey
authors.forename: M J
authors.initials: MJ
authors.lastname: Lind
authors.forename: M
authors.initials: M
authors.lastname: Green
authors.forename: J
authors.initials: J
authors.lastname: Hines
authors.forename: A
authors.initials: A
authors.lastname: Johnstone
authors.forename: N
authors.initials: N
authors.lastname: Clendeninn
authors.forename: A H
authors.initials: AH
authors.lastname: Calvert
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005069:Evaluation Studies as Topic; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013940:Thymidylate Synthase; C099178:nolatrexed