A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis.
A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis.
复制标题
DOI：
10.1016/j.clml.2013.11.001
复制
发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Kantarjian H
中科院分区：
文献类型：
--
作者：
Foran J;Ravandi F;Wierda W;Garcia-Manero G;Verstovsek S;Kadia T;Burger J;Yule M;Langford G;Lyons J;Ayrton J;Lock V;Borthakur G;Cortes J;Kantarjian H
确定Aurora激酶A和B抑制剂AT 9283在复发性或难治性白血病患者中的MTD。其他终点包括药代动力学、安全性和耐受性、药效学和疗效的初步证据。AT 9283每21天连续输注72小时。通过标准3+3设计递增剂量。确定72小时输注的MTD后，输注持续时间递增至96小时和120小时。总计48例患者接受了≥1个周期的AT 9283治疗。中位年龄为61岁（范围22-86岁），56%的男性，75%诊断为AML，89%既往接受过≥3线（最多16线）治疗。确定324 mg/m2/72 h AT 9283为MTD。DLT为心肌梗死、高血压、心肌病、肿瘤溶解综合征、肺炎和多器官衰竭。其他AT 9283相关毒性（非DLT）包括骨髓抑制，主要是白细胞减少症和粘膜炎。大约三分之一的复发性/难治性AML患者接受AT 9283治疗后，骨髓原始细胞减少≥38%;然而，尽管有极光激酶B抑制的证据，但这种效应是一过性的，未达到客观缓解。2例加速期CML患者显示获益证据，1例表现为细胞遗传学缓解; 1例患者完成6个周期治疗。AT 9283的暴露量通常与剂量成比例。AT 9283的耐受性具有强烈的剂量依赖性，可逆性骨髓抑制在较低剂量下占主导地位，而心血管毒性等事件在较高剂量下出现。正在其他患者人群中进行AT 9283的临床试验。
To identify the MTD of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics and preliminary evidence of efficacy. AT9283 was administered as a continuous 72h infusion every 21 days. Doses were escalated by a standard 3+3 design. After the MTD for the 72h infusion was identified, infusion duration was increased incrementally to 96h and 120h. In total, 48 patients received ≥1 cycle of AT9283. Median age was 61 years (range 22–86 years), with 56% men, 75% diagnosed with AML, and 89% having received ≥3 (up to 16) prior lines of therapy. 324 mg/m2/72h AT9283 was determined to be the MTD. DLTs were myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia and multiorgan failure. Other AT9283-related toxicities (non-DLT) included myelosuppression, predominantly leucopenia and mucositis. Bone marrow blasts decreased ≥38% after AT9283 treatment in approximately one-third of patients with relapsed/refractory AML; however, this effect was transient and no objective responses were achieved, despite evidence of aurora kinase B inhibition. Two patients with accelerated phase CML showed evidence of benefit, manifest as a cytogenetic response in one case; one patient completed 6 cycles of treatment. Exposure to AT9283 was generally dose proportional. AT9283 tolerability was strongly dose dependent with reversible myelosuppression predominating at lower doses and events such as cardiovascular toxicities manifesting at higher doses. Clinical trials with AT9283 are ongoing in alternative patient populations.
登录
查看更多内容
影响因子：
3.7
作者：
Failes TW;Mitic G;Abdel-Halim H;Po'uha ST;Liu M;Hibbs DE;Kavallaris M
通讯作者：
Kavallaris M
影响因子：
6.5
作者：
Farag SS
通讯作者：
Farag SS
影响因子：
3.7
作者：
Barosi G;Poletto V;Massa M;Campanelli R;Villani L;Bonetti E;Viarengo G;Catarsi P;Klersy C;Rosti V
通讯作者：
Rosti V
DOI：
10.1073/pnas.0504952102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Carter, TA;Wodicka, LM;Lockhart, DJ
通讯作者：
Lockhart, DJ
影响因子：
20.3
作者：
Lowenberg, Bob;Muus, Petra;Kantarjian, Hagop
通讯作者：
Kantarjian, Hagop