title: Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias.
abstract: OBJECTIVE
  Troxacitabine has significant single-agent activity. This study was conducted to define the dose-limiting toxicities (DLTs) of its combination with cytarabine (ara-C), idarubicin, or topotecan.
  
  
  METHODS
  Patients with refractory acute myeloid leukemia (AML), advanced myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were initially randomly assigned to receive troxacitabine 5.0 mg/m(2) by intravenous (IV) infusion over 30 minutes on days 1 to 5 with ara-C 1.0 g/m(2)/d IV [DOSAGE ERROR CORRECTED] over 2 hours on days 1 to 5, idarubicin 12 mg/m(2) by 5 minute IV infusion on days 1 to 3, or topotecan 1.0 mg/m(2) as an continuous IV infusion on days 1 to 5. Doses were then adjusted to define DLT for each combination.
  
  
  RESULTS
  Eighty-seven patients (68 AML, eight MDS, 11 CML-BP) were treated. DLTs were hepatic transaminitis, hyperbilirubinemia, and hand foot syndrome (HFS) on the troxacitabine plus ara-C combination. The recommended phase II doses were 6 mg/m(2) once a day for 5 days and 1.0g/m(2) once a day for 5 days, respectively. DLTs were diarrhea, rash, and mucositis on the troxacitabine plus topotecan combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 0.75 mg/m(2) once a day for 5 days, respectively. DLTs were HFS, rash, and mucositis on the troxacitabine plus idarubicin combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 9 mg/m(2) once a day for 3 days, respectively. Among 74 evaluable patients with AML or MDS, 10 (13%) achieved complete remission and four (5%) had hematologic improvement. Two of 11 (18%) evaluable patients with CML-BP returned to chronic phase.
  
  
  CONCLUSIONS
  Troxacitabine-based combinations had significant antileukemic activity.
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. frankgiles@aol.com
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Dan
authors.initials: D
authors.lastname: Douer
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Levine
authors.forename: Charles A
authors.initials: CA
authors.lastname: Koller
authors.forename: Sima S
authors.initials: SS
authors.lastname: Jeha
authors.forename: Susan M
authors.initials: SM
authors.lastname: O'Brien
authors.forename: Elihu H
authors.initials: EH
authors.lastname: Estey
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004148:Dioxolanes / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D004148:Dioxolanes; D003561:Cytarabine; C074908:troxacitabine; D019772:Topotecan; D003596:Cytosine; D015255:Idarubicin