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- Title
A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia.
- Authors
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
- 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.
- Subjects
QUINOLONE antibacterial agents; CANCER treatment; ACUTE leukemia; PHARMACOKINETICS; DRUG dosage; PATIENTS; HETEROCYCLIC compounds; THIAZOLES; CANCER relapse; DRUG resistance in cancer cells; LONGITUDINAL method; LYMPHOBLASTIC leukemia; TUMOR classification; ACUTE myeloid leukemia; TREATMENT effectiveness; SALVAGE therapy; THERAPEUTICS
- Publication
Leukemia (08876924), 2011, Vol 25, Issue 12, p1808
- ISSN
0887-6924
- Publication type
journal article
- DOI
10.1038/leu.2011.157