A Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors.
A Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors.
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DOI：
10.1007/s10637-012-9904-9
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发表时间：
2013-04
影响因子：
3.4
通讯作者：
Agus, David B.
中科院分区：
文献类型：
--
作者：
Gordon, Michael S.;Mendelson, David S.;Gross, Mitchell;Uttenreuther-Fischer, Martina;Ould-Kaci, Mahmoud;Zhao, Yihua;Stopfer, Peter;Agus, David B.
本试验评价了阿法替尼（一种新型ErbB家族阻滞剂）的安全性、耐受性和最大耐受剂量（MTD）。方法在这项开放标签、剂量递增的I期研究中，阿法替尼连续口服给药，每日一次，持续28天，用于晚期或转移性实体瘤患者。以3 + 3设计进行剂量递增，起始剂量为10 mg/天（d）;每个连续队列的剂量加倍，直至确定MTD。MTD队列扩展至总计19例患者。评估了不良事件（AE）的发生率和严重程度、抗肿瘤活性和药代动力学。结果30例患者接受了至少一剂阿法替尼治疗。29例患者可评价缓解。在接受60 mg/d治疗的2/3例患者中观察到剂量限制性毒性（DLT），包括3级腹泻。MTD确定为40 mg/d。最常见的治疗相关AE为腹泻和粘膜炎症，分别有76.7%和43.3%的患者报告。5名患者病情稳定，中位无进展生存期为111天。未出现客观反应。药代动力学数据显示，最迟在第8天未偏离剂量比例性并达到稳态。结论：阿法替尼40 mg每日一次连续给药耐受性良好，副作用可控。
Background This trial evaluated the safety, tolerability and maximum tolerated dose (MTD) of afatinib, a novel ErbB Family Blocker. Methods In this open-label, dose-escalation Phase I study, afatinib was administered continuously, orally, once-daily for 28 days to patients with advanced or metastatic solid tumors. Dose escalation was performed in a 3 + 3 design, with a starting dose of 10 mg/day (d); doses were doubled for each successive cohort until the MTD was defined. The MTD cohort was expanded to a total of 19 patients. Incidence and severity of adverse events (AEs), antitumor activity and pharmacokinetics were assessed. Results Thirty patients received at least one dose of afatinib. Twenty-nine patients were evaluable for response. Dose-limiting toxicities (DLTs) consisting of Grade 3 diarrhea were observed in two out of three patients treated at 60 mg/d. The MTD was determined at 40 mg/d. The most frequent treatment-related AEs were diarrhea and mucosal inflammation reported in 76.7 % and 43.3 % of patients respectively. Five patients had stable disease with a median progression-free survival of 111 days. No objective responses occurred. Pharmacokinetic data showed no deviation from dose-proportionality and steady-state was reached on Day 8 at the latest. Conclusions Afatinib was well tolerated with manageable side effects when administered once-daily, continuously at a dose of 40 mg.
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影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro
影响因子：
51.1
作者：
Miller, Vincent A.;Hirsh, Vera;Yang, James Chih-Hsin
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影响因子：
3.8
作者：
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影响因子：
158.5
作者：
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通讯作者：
Fukuoka, Masahiro
影响因子：
158.5
作者：
Rosell, Rafael;Moran, Teresa;Taron, Miquel
通讯作者：
Taron, Miquel