AZD1480: A Phase I Study of a Novel JAK2 Inhibitor in Solid Tumors
AZD1480: A Phase I Study of a Novel JAK2 Inhibitor in Solid Tumors
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DOI：
10.1634/theoncologist.2013-0198
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发表时间：
2013-07-01
期刊：
影响因子：
5.8
通讯作者：
Eckhardt, S. Gail
中科院分区：
文献类型：
--
作者：
Plimack, Elizabeth R.;LoRusso, Patricia M.;Eckhardt, S. Gail
背景：AZD 1480是一种抑制Janus相关激酶1和2（JAK 1和JAK 2）的新药。本I期研究的主要目的是研究AZD 1480单药治疗实体瘤患者的安全性和耐受性。方法：38例晚期恶性肿瘤患者接受10-70 mg每日一次（QD）和20-45 mg每日两次（b.i.d.）治疗。结果：药代动力学（PK）分析显示，QD或b.i.d.重复给药后，吸收和消除迅速，蓄积极少。剂量。暴露量在10-50 mg范围内呈剂量依赖性增加。达到的最大血药浓度（C-max）与给药后1小时相似，t（1/2）与5小时相似。循环粒细胞的药效学分析表明，给药后1-2小时，磷酸化STAT 3（pSTAT 3）抑制最大，与Cmax一致，并且在较高剂量下pSTAT 3抑制更大。在稳态药物水平下，在最高试验剂量70 mg QD下，粒细胞中的平均pSTAT 3抑制为56%（标准差：+/- 21%）。剂量限制性毒性（DLT）包括多效性神经系统不良事件（AE），包括头晕、焦虑、共济失调、记忆丧失、幻觉和行为改变。这些不良事件通常是可逆的剂量减少或治疗county.Conclusions：DLT是否是由于抑制JAK-1/2或脱靶效应是未知的。异常DLT和缺乏临床活性导致开发中止。
Background: AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). The primary objective of this phase I study was to investigate the safety and tolerability of AZD1480 when administered as monotherapy to patients with solid tumors.Methods: Thirty-eight patients with advanced malignancies were treated at doses of 10-70 mg once daily (QD) and 20-45 mg b.i.d..Results: Pharmacokinetic (PK) analysis revealed rapid absorption and elimination with minimal accumulation after repeated QD or b.i.d. dosing. Exposure increased in a dose-dependent manner from 10-50 mg. Maximum plasma concentration (C-max) was attained similar to 1 hour after dose, and t(1/2) was similar to 5 hours. Pharmacodynamic analysis of circulating granulocytes demonstrated maximum phosphorylated STAT3 (pSTAT3) inhibition 1-2 hours after dose, coincident with Cmax, and greater pSTAT3 inhibition at higher doses. The average pSTAT3 inhibition in granulocytes at the highest dose tested, 70 mg QD, was 56% (standard deviation: +/- 21%) at steady-state drug levels. Dose-limiting toxicities (DLTs) consisted of pleiotropic neurologic adverse events (AEs), including dizziness, anxiety, ataxia, memory loss, hallucinations, and behavior changes. These AEs were generally reversible with dose reduction or treatment cessation.Conclusions: Whether the DLTs were due to inhibition of JAK-1/2 or to off-target effects is unknown. The unusual DLTs and the lack of clinical activity led to discontinuation of development.