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 language | English (US) |
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Pages (from-to) | 1808-1814 |
Number of pages | 7 |
Journal | Leukemia |
Volume | 25 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2011 |
Externally published | Yes |
Keywords
- acute leukemia
- phase 1
- quinolone derivative
- relapsed/refractory
- voreloxin
- vosaroxin
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research