A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia

J. E. Lancet, F. Ravandi, R. M. Ricklis, L. D. Cripe, H. M. Kantarjian, F. J. Giles, A. F. List, T. Chen, R. S. Allen, J. A. Fox, G. C. Michelson, J. E. Karp

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m 2; MTD was 72 mg/m 2. Twice-weekly schedule: 31 patients received 9-50 mg/m 2; MTD was 40 mg/m 2. DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to 5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 mol/l plasma vosaroxin concentration (P0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m 2. The average terminal half-life was ∼25h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.

Original languageEnglish (US)
Pages (from-to)1808-1814
Number of pages7
JournalLeukemia
Volume25
Issue number12
DOIs
StatePublished - Dec 2011

Keywords

  • acute leukemia
  • phase 1
  • quinolone derivative
  • relapsed/refractory
  • voreloxin
  • vosaroxin

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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    Lancet, J. E., Ravandi, F., Ricklis, R. M., Cripe, L. D., Kantarjian, H. M., Giles, F. J., List, A. F., Chen, T., Allen, R. S., Fox, J. A., Michelson, G. C., & Karp, J. E. (2011). A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia. Leukemia, 25(12), 1808-1814. https://doi.org/10.1038/leu.2011.157