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Invest New Drugs ; 30(3): 1107-15, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21494838

RESUMO

Eg5 (kinesin spindle protein) is a microtubule motor protein, essential for centrosome separation during mitosis. This Phase I/II, open-label, multicenter, two-part study investigated AZD4877, a potent Eg5 inhibitor, in patients with acute myeloid leukemia. Primary objectives were to determine the maximum tolerated dose (MTD) (part A), assess efficacy (part B) and determine the pharmacokinetic profile (parts A and B). Secondary objectives included assessment of safety and tolerability. AZD4877 was administered at a range of doses (2, 4, 7, 10, 13, 16 and 18 mg/day) as a 1-hour intravenous infusion on three consecutive days of a continuous 2-week schedule. The MTD in part A was defined as 16 mg/day based on dose-limiting stomatitis at 16 and 18 mg/day, hyperbilirubinemia at 16 mg/day and palmar-plantar erythrodysesthesia syndrome at 18 mg/day. Systemic exposure to AZD4877 generally increased with increasing dose whereas half-life was not dose dependent. No evaluable patients experienced a complete remission (CR) or CR with incomplete blood count recovery (CRi), demonstrating no evidence of AZD4877 efficacy in this population. Evidence of monoasters in all but the 4 mg/day dose group provided proof of mechanism for AZD4877. This study was terminated due to lack of efficacy. (ClinicalTrials.gov identifier NCT00486265).


Assuntos
Antimitóticos/administração & dosagem , Benzamidas/administração & dosagem , Cinesinas/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Pirimidinonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimitóticos/efeitos adversos , Antimitóticos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Adulto Jovem
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