title: A phase I study of the antimetabolite (E)-2'-fluoromethylene-2'-deoxycytidine (MDL 101,731) administered as a twice-weekly infusion.
abstract: OBJECTIVE
  (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite. Preclinical tests have shown antiproliferative activity in various human tumor xenograft models and have also indicated that efficacy is greatest with frequent dosing schedules. We conducted a phase I trial of MDL 101,731 infusion in humans with advanced cancer to determine the maximum tolerated dose and the dose-limiting toxicities of this drug when administered on a twice-weekly schedule.
  
  
  METHODS
  The drug was administered on a twice-weekly schedule for 3 weeks, followed by a 2-week rest. The initial dose was 16 mg/m2. This was reduced to 12 mg/m2 if persistent neutropenia occurred. All toxicity in the first six patients resolved by the end of the first rest week. The schedule was changed to 3 weeks of therapy followed by 1 rest week for the subsequent four patients.
  
  
  RESULTS
  Dose escalation beyond 16 mg/m2 was not feasible because of dose-limiting toxicities, principally hematologic. No irreversible or life-threatening toxicity was seen. Grade 2 noninfectious fever, mucositis, and anorexia were also seen. In patients with stable disease, there was a heavily pretreated patient with rectal cancer in whom a 38% reduction in indicator lesions of 7 months' duration occurred.
  
  
  CONCLUSIONS
  (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite with evidence of anticancer activity in heavily pretreated patients. The maximum tolerated dose when the agent is given twice weekly is 16 mg/m2.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8032, USA.
authors.forename: B
authors.initials: B
authors.lastname: Burtness
authors.forename: M
authors.initials: M
authors.lastname: Belker
authors.forename: M
authors.initials: M
authors.lastname: Stoltz
authors.forename: K M
authors.initials: KM
authors.lastname: Peccerillo
authors.forename: L A
authors.initials: LA
authors.lastname: Lamb
authors.forename: S E
authors.initials: SE
authors.lastname: Chmael
authors.forename: A
authors.initials: A
authors.lastname: McKeon
authors.forename: M B
authors.initials: MB
authors.lastname: Clark
authors.forename: J
authors.initials: J
authors.lastname: Winship
authors.forename: J C
authors.initials: JC
authors.lastname: Marsh
authors.forename: G
authors.initials: G
authors.lastname: Pizzorno
authors.forename: V T
authors.initials: VT
authors.lastname: DeVita
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; C086432:tezacitabine