title: A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia.
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.
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. jeffrey.lancet@moffitt.org
authors.forename: J E
authors.initials: JE
authors.lastname: Lancet
authors.forename: F
authors.initials: F
authors.lastname: Ravandi
authors.forename: R M
authors.initials: RM
authors.lastname: Ricklis
authors.forename: L D
authors.initials: LD
authors.lastname: Cripe
authors.forename: H M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: F J
authors.initials: FJ
authors.lastname: Giles
authors.forename: A F
authors.initials: AF
authors.lastname: List
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.forename: R S
authors.initials: RS
authors.lastname: Allen
authors.forename: J A
authors.initials: JA
authors.lastname: Fox
authors.forename: G C
authors.initials: GC
authors.lastname: Michelson
authors.forename: J E
authors.initials: JE
authors.lastname: Karp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009287:Naphthyridines / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009367:Neoplasm Staging; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016879:Salvage Therapy; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D009287:Naphthyridines; D013844:Thiazoles; C485113:vosaroxin