title: [Phase I study of raltitrexed (ZD-1694)].
abstract: A multicenter cooperative phase I study of ZD-1694 (raltitrexed), a novel, folate-based thymidylate synthase (TS) inhibitor, was conducted with single and repeated doses in 30 patients with various malignant tumors. ZD-1694 was intravenously infused over 15 minutes. In the single-dose study, the initial dose was fixed at 1.0 mg/m2 (1n), and the dose was escalated stepwise up to 3.5 mg/m2 (3.5 n). Based on the results of the single-dose study, in the repeated-dose study, doses of 2.5 n and 3 n were infused every three weeks (3 weeks/one course). In principle, patients received 2 courses or more. Of the 29 eligible patients, 16 were in the single-dose study and 13 in the repeated-dose study. Adverse reactions were evaluated in all eligible patients. In the single-dose study, neutropenia, nausea/vomiting, diarrhea, and transaminase (GOT, GPT) increases, of grade 3 or higher, occurred at high doses of 3 n and 3.5 n. These were regarded as dose-limiting toxicities (DLT). DLT of grade 3 or higher were observed in 1 of 4 patients given 3 n and 2 of 4 patients given 3.5 n. These results suggested that the maximum tolerated dose (MTD) of ZD-1694 was 3.5 n (3.5 mg/m2). In the repeated-dose study, DLT of grade 3 or higher was observed in no more than one third of each dose group, 2 of the 6 patients given 2.5 n and 2 of the 7 patients given 3 n. These results suggested that 3 n (3.0 mg/m2), a dose nearer to MTD, was the recommended dose for the phase II study. Although transaminase increases were observed in all patients, in 12 of them the increase was grade 2 or lower and reversible. A pharmacokinetic investigation showed the mean elimination half life of ZD-1694 plasma concentration was 91.5 hours in the single-dose group and 119.1 hours in the repeated dose group. It was suggested that ZD-1694 is metabolized to polyglutamates after uptake and retained in the cells for a long duration. However, no accumulation was seen in plasma concentration of ZD-1694 following repeated doses at 3-weekly intervals. One PR was observed in a patient with colorectal cancer receiving 2.5 n in the repeated-dose study. Based on these results, the recommended dosage and administration for the phase II study of ZD-1694 was 3 n (3.0 mg/m2) intravenously infused over 15 minutes every 3 weeks.
authors.affiliation: Dept. of Pulmonary Medicine, Osaka City General Hospital.
authors.forename: N
authors.initials: N
authors.lastname: Horikoshi
authors.forename: K
authors.initials: K
authors.lastname: Aiba
authors.forename: M
authors.initials: M
authors.lastname: Fukuoka
authors.forename: S
authors.initials: S
authors.lastname: Akazawa
authors.forename: Y
authors.initials: Y
authors.lastname: Sakata
authors.forename: K
authors.initials: K
authors.lastname: Furuse
authors.forename: R
authors.initials: R
authors.lastname: Kanamaru
authors.forename: S
authors.initials: S
authors.lastname: Kudoh
authors.forename: T
authors.initials: T
authors.lastname: Konishi
authors.forename: M
authors.initials: M
authors.lastname: Kurihara
authors.forename: H
authors.initials: H
authors.lastname: Niitani
authors.forename: H
authors.initials: H
authors.lastname: Furue
authors.forename: S
authors.initials: S
authors.lastname: Tsukagoshi
authors.forename: T
authors.initials: T
authors.lastname: Taguchi
authors.forename: S
authors.initials: S
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Ota
authors.forename: T
authors.initials: T
authors.lastname: Kotake
authors.forename: A
authors.initials: A
authors.lastname: Wakui
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000855:Anorexia / Q000139:chemically induced; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D003110:Colonic Neoplasms / Q000188:drug therapy; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C068874:raltitrexed