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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 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/m2. Twice-weekly schedule: 31 patients received 9-50 mg/m 2; MTD was 40 mg/m2. 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/m2. 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
  • Oncology
  • Cancer Research

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