Division of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
Br J Cancer. 2012 Feb 14;106(4):666-72. doi: 10.1038/bjc.2011.590. Epub 2012 Jan 12.
This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2.
The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks.
In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d.
The toxicity profile and PK properties of oral TAK-285 warrant further evaluation.
这项 I 期首次人体研究在日本患者中进行，旨在研究口服 TAK-285 的安全性、药代动力学（PKs），并确定最大耐受剂量（MTD）。TAK-285 是一种新型的双重 erbB 蛋白激酶抑制剂，专门针对人类表皮生长因子受体（EGFR）和 HER2。
TAK-285 剂量递增，直至确定 MTD。第二组患者接受 MTD 下的 TAK-285 至少 4 周。
共有 26 名患者接受了 TAK-285 50-400mg 每日一次（qd）或每日两次（bid）的剂量治疗；20 名患者组成剂量递增队列，其余 6 名患者为重复给药队列。TAK-285 具有良好的耐受性。两名接受 400mg bid 的患者出现剂量限制毒性，分别为 3 级氨基转移酶升高和 3 级食欲下降。因此，确定 MTD 为 300mg bid。口服 TAK-285 后吸收迅速，稳态时的血浆暴露量呈剂量比例增加，剂量范围为 50-300mg bid。一名接受 300mg bid 的腮腺癌患者观察到部分缓解。
口服 TAK-285 的毒性特征和 PK 特性值得进一步评估。
