Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia.
Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia.
复制标题
DOI：
10.1007/s10637-011-9660-2
复制
发表时间：
2012-06
影响因子：
3.4
通讯作者：
Minden, M.
中科院分区：
文献类型：
--
作者：
Kantarjian, H. M.;Padmanabhan, S.;Stock, W.;Tallman, M. S.;Curt, G. A.;Li, J.;Osmukhina, A.;Wu, K.;Huszar, D.;Borthukar, G.;Faderl, S.;Garcia-Manero, G.;Kadia, T.;Sankhala, K.;Odenike, O.;Altman, J. K.;Minden, M.
驱动蛋白纺锤体蛋白（Eg 5）是一种微管运动蛋白，在有丝分裂过程中对中心体分离至关重要。这项I/II期、开放标签、多中心、两部分研究调查了AZD 4877（一种强效Eg 5抑制剂）在急性髓性白血病患者中的作用。主要目的是确定最大耐受剂量（MTD）（A部分）、评估疗效（B部分）和确定药代动力学特征（A和B部分）。次要目的包括安全性和耐受性评估。AZD 4877以一系列剂量（2、4、7、10、13、16和18 mg/天）静脉输注给药，每次1小时，连续给药3天，连续给药2周。基于16和18 mg/天剂量限制性口腔炎、16 mg/天高胆红素血症和18 mg/天掌跖红肿综合征，A部分的MTD定义为16 mg/天。AZD 4877的全身暴露量通常随剂量增加而增加，而半衰期无剂量依赖性。无可评价患者出现完全缓解（CR）或CR伴血细胞计数不完全恢复（CRi），表明该人群中无AZD 4877疗效证据。除4 mg/天剂量组外，所有剂量组均存在单囊动物的证据，为AZD 4877的作用机制提供了证据。该研究因缺乏疗效而终止。
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.
登录
查看更多内容
影响因子：
6
作者：
Masuda, A;Maeno, K;Takahashi, T
通讯作者：
Takahashi, T
影响因子：
11.2
作者：
Sakowicz, R;Finer, JT;Wood, KW
通讯作者：
Wood, KW
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
64.5
作者：
Taylor, SS;McKeon, F
通讯作者：
McKeon, F
影响因子：
6.2
作者：
Kantarjian, H;O'Brien, S;Estey, E
通讯作者：
Estey, E