Phase I and pharmacologic study of oral (E)-2'-deoxy-2'-(fluoromethylene) cytidine: on a daily x 5-day schedule

• Published in: Investigational new drugs 1998, Vol.16 (3), p.245
• Main Authors: Masuda, N, Negoro, S, Takeda, K, Takifuji, N, Hirashima, T, Yana, T, Kurata, N, Kuwabara, T, Kobayashi, S, Kudoh, S, Matsui, K, Takada, M, Fukuoka, M
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Antibodies; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biochemistry; Blood tests; Carcinoma, Non-Small-Cell Lung - drug therapy; Chemotherapy; Creatinine; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacokinetics; Deoxycytidine - therapeutic use; Drug Administration Schedule; Drug dosages; Female; Humans; Lung cancer; Lung Neoplasms - drug therapy; Male; Middle Aged; Neutropenia; Patients; Pharmacokinetics; Plasma; Ribonucleoside Diphosphate Reductase - antagonists & inhibitors; Ribonucleotide reductase; Tomography; Toxicity; Tumors; Urinalysis
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1023/A:1006126212481

(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3-4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.