title: Phase I/II study of continuous-infusion troxacitabine in refractory acute myeloid leukemia.
abstract: OBJECTIVE
  Troxacitabine is a non-natural nucleoside analog with unique structural and metabolic features. Bolus intravenous (IV) troxacitabine regimens have shown significant activity in patients with refractory acute myeloid leukemia (AML) and preclinical data suggest that administration via continuous infusion may result in enhanced antitumor activity.
  
  
  METHODS
  Patients with refractory AML initially received troxacitabine 10.1 mg/m2 by continuous IV infusion (CIVI) for 48 hours. Infusion duration and daily dose were increased in subsequent patient cohorts.
  
  
  RESULTS
  Forty-eight patients, median age 58 years (range, 21 to 81 years), were treated. Dose-limiting toxicities were mucositis and hand-foot syndrome, and 12.0 mg/m2/d for 5 days was established as the maximum-tolerated dose. Seven patients (15%) achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), with a median survival among responders of 12 months. Steady-state concentrations of troxacitabine were found to be linearly and inversely proportionally related to calculated creatinine clearance at doses of 10.1 and 12.0 mg/m2/d. All patients responding to troxacitabine had steady-state serum drug concentration of more than approximately 80 ng/mL. In 27 patients achieving target troxacitabine plasma concentrations (ie, approximately 80 ng/mL) the CR + CRp rate was 26%.
  
  
  CONCLUSIONS
  Troxacitabine administered as a CIVI allows a significant increase in dose-intensity in comparison to IV bolus regimens, has antileukemic activity, and warrants additional investigation in patients with refractory AML. The recommended phase II study dose is 12.0 mg/m2 daily CIVI for 5 days.
authors.affiliation: Weill Medical College of Cornell University, The New York Presbyterian Hospital, New York, NY 10021, USA. gar2001@med.cornell.edu
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Ritchie
authors.forename: Sandra
authors.initials: S
authors.lastname: Allen-Bard
authors.forename: Tania J
authors.initials: TJ
authors.lastname: Curcio
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Wilkes
authors.forename: S Lani
authors.initials: SL
authors.lastname: Park
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelner
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Feldman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004148:Dioxolanes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine