期刊
ONCOLOGIST
卷 18, 期 7, 页码 819-820出版社
ALPHAMED PRESS
DOI: 10.1634/theoncologist.2013-0198
关键词
-
类别
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据