title: A Phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors.
abstract: The purpose of this study was to perform a Phase I trial of raltitrexed, a selective inhibitor of thymidylate synthase, and to determine the pharmacokinetic and toxicity profiles as a function of raltitrexed dose. Fifty patients with advanced solid tumors and good performance status were treated with raltitrexed as a 15-min i.v. infusion every 3 weeks, at doses escalating from 0.6 to 4.5 mg/m2. Asthenia, neutropenia, and hepatic toxicity were the most common dose-limiting toxicities in this largely pretreated patient population, but they occurred during the initial cycle in only one of nine patients treated with 4.0 mg/m2 and in two of nine patients treated with 4.5 mg/m2. Only 2 of 13 patients treated with 3.5 mg/m2 ultimately experienced unacceptable toxicity after three and seven cycles, compared with 42 and 56% of patients receiving 4.0 and 4.5 mg/m2 after medians of three and two cycles, respectively. The maximum raltitrexed plasma concentration and the area under the plasma concentration-time curve increased in proportion to dose. Raltitrexed clearance was independent of dose and was associated with the estimated creatinine clearance. Asthenia, neutropenia, and hepatic transaminitis were dose-related and tended to occur more frequently when patients received three or more cycles of therapy. A 3-week treatment interval was feasible in the majority of patients at all doses. Although 4.0 mg/m2 appeared to be a safe starting dose in this pretreated patient population, about half who received two or more courses ultimately experienced dose-limiting toxicity. A dose of 3.5 mg/m2 was well tolerated in most patients.
authors.affiliation: National Cancer Institute-Medicine Branch, National Naval Medical Center, Bethesda, Maryland 20889-5105, USA. jgrem@helix.nih.gov
authors.forename: J L
authors.initials: JL
authors.lastname: Grem
authors.forename: J M
authors.initials: JM
authors.lastname: Sorensen
authors.forename: E
authors.initials: E
authors.lastname: Cullen
authors.forename: C H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: A P
authors.initials: AP
authors.lastname: Chen
authors.forename: J M
authors.initials: JM
authors.lastname: Hamilton
authors.forename: S G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: N
authors.initials: N
authors.lastname: McAtee
authors.forename: D
authors.initials: D
authors.lastname: Lawrence
authors.forename: B
authors.initials: B
authors.lastname: Goldspiel
authors.forename: P G
authors.initials: PG
authors.lastname: Johnston
authors.forename: C J
authors.initials: CJ
authors.lastname: Allegra
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011799:Quinazolines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013876:Thiophenes / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; C068874:raltitrexed