Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias.
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.
Giles
Francis J
FJ
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. frankgiles@aol.com
Faderl
Stefan
S
Thomas
Deborah A
DA
Cortes
Jorge E
JE
Garcia-Manero
Guillermo
G
Douer
Dan
D
Levine
Alexandra M
AM
Koller
Charles A
CA
Jeha
Sima S
SS
O'Brien
Susan M
SM
Estey
Elihu H
EH
Kantarjian
Hagop M
HM
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
D004148:Dioxolanes; D003561:Cytarabine; C074908:troxacitabine; D019772:Topotecan; D003596:Cytosine; D015255:Idarubicin