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Randomized Phase I/II Study of Troxacitabine Combined With Cytarabine, Idarubicin, or Topotecan in Patients With Refractory Myeloid Leukemias

From the Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Division of Hematology, University of Southern California Keck Medical School; and Norris Cancer Center, Los Angeles, CA.

Address reprint requests to Francis J. Giles, MD, The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia, 1400 Holcombe Blvd., Box 428, Houston, TX 77030; email: frankgiles{at}aol.com.

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/m² by 5 minute IV infusion on days 1 to 3, or topotecan 1.0 mg/m² 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/m² 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.

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