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

Leukemia. 2011 Dec;25(12):1808-14. doi: 10.1038/leu.2011.157. Epub 2011 Jul 15.

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 μmol/l plasma vosaroxin concentration (P<0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m(2). The average terminal half-life was ~25 h 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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Follow-Up Studies
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Male
  • Middle Aged
  • Naphthyridines / therapeutic use*
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Staging
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Salvage Therapy*
  • Thiazoles / therapeutic use*
  • Treatment Outcome
  • Young Adult

Substances

  • Naphthyridines
  • Thiazoles
  • vosaroxin