Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias

Purpose: 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. Patients and 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/m² by intravenous (IV) infusion over 30 minutes on days 1 to 5 with ara-C 1.0 mg/m²/d IV 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/m² once a day for 5 days and 1.0g/m² 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/m² once a day for 5 days and 0.75 mg/m² 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/m² 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. Conclusion: Troxacitabine-based combinations had significant antileukemic activity.