Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors
Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors
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DOI：
10.1093/annonc/mdq344
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发表时间：
2011-02-01
影响因子：
50.5
通讯作者：
Schellens, J. H.
中科院分区：
文献类型：
--
作者：
Boss, D. S.;Witteveen, P. O.;Schellens, J. H.
背景：确定极光B激酶抑制剂AZD1152在两种给药方案下的剂量限制毒性（DLT）和最大耐受剂量（MTD），并评估其安全性、生物活性和药代动力学（PK）。患者和方法：晚期实体恶性肿瘤患者接受逐步递增剂量（100-650 mg）的AZD1152治疗，每7天(a)或14天(B)输注2小时。评估不良事件（ae）、PK变量和肿瘤反应。结果：治疗59例；附表A 19种，附表b 40种，总残留量分别为200毫克和450毫克。中性粒细胞减少（伴/不伴发热）是各方案中最常见的AE和DLT。不良事件的通用术语标准3.0级>= 3，在方案A中分别有58%和11%的患者出现中性粒细胞减少症和白细胞减少症，在方案b中分别有43%和20%的患者出现中性粒细胞减少症和白细胞减少症。在任何剂量或方案下均未观察到客观的肿瘤反应，尽管根据RECIST的定义，总体上有15名患者（25%）达到了稳定的疾病。AZD1152- hqpa（活性药物）输注1小时后，系统暴露于AZD1152，呈现线性pk。结论：AZD1152总体耐受良好，中性粒细胞减少是最常见的AE和DLT。AZD1152的活性药物AZD1152- hqpa与暴露呈线性关系。
Background: To determine, for each of two dosing schedules, the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of AZD1152, an Aurora B kinase inhibitor, and to evaluate its safety, biologic activity and pharmacokinetics (PK).Patients and methods: Patients with advanced solid malignancies were treated with escalating doses (100-650 mg) of AZD1152, administered as a 2-h infusion every 7 days (A) or 14 days (B). Adverse events (AEs), PK variables and tumor response were assessed.Results: Fifty-nine patients were treated; 19 in schedule A and 40 in schedule B. The MTDs were 200 and 450 mg, respectively. Neutropenia (with/without fever) was the most frequent AE and DLT in each schedule. Common Terminology Criteria of Adverse Events version 3.0 grade >= 3 neutropenia and leukopenia occurred in 58% and 11% of patients, respectively, in schedule A and 43% and 20%, respectively, in schedule B. No objective tumor responses were observed at any dose or schedule, although stable disease, as defined by RECIST, was achieved in 15 patients (25%) overall. Systemic exposure to AZD1152-hQPA (active drug) was observed by 1 h into the infusion and exhibited linear PK.Conclusions: AZD1152 was generally well tolerated with neutropenia being the most frequently reported AE and DLT. Exposure to AZD1152-hQPA, the active drug of AZD1152, was linear.