Yamamoto Noboru, Horiike Atsushi, Fujisaka Yasuhito, Murakami Haruyasu, Shimoyama Tatsu, Yamada Yasuhide, Tamura Tomohide
Division of Internal Medicine, National Cancer Center Hospital, 5-1-1, Tsukiji Chuo-ku, Tokyo 104-0045, Japan.
Cancer Chemother Pharmacol. 2008 Mar;61(3):489-96. doi: 10.1007/s00280-007-0494-8. Epub 2007 May 5.
The objectives of this phase I dose-finding study of erlotinib were to investigate the toxicity profile, to confirm the acceptable toxicity of doses up to 150 mg/day, and to assess the pharmacokinetic (PK) profile and antitumor activity in Japanese patients with solid tumors.
Patients with solid tumors not amenable to standard forms of treatment were included. Treatment cycle 1 consisted of single-dose administration on day 1, withdrawal on day 2, continuous daily administration from days 3-23, and withdrawal from days 24-30. Subsequent cycles (28 days) used continuous daily administration. The dose of erlotinib was escalated from 50 mg/day to 150 mg/day in 50-mg increments. PK evaluation was performed in all patients during cycle 1.
Fifteen patients, aged 38-70 (median; 57) years with non-small-cell lung (n = 11), colorectal (n = 3) or head and neck (n = 1) cancer were enrolled. The major toxicities were rash, diarrhea and liver dysfunctions, which were generally mild and easily manageable. The good tolerability of erlotinib up to the dose of 150 mg/day was confirmed. One patient developed grade 5 treatment-related interstitial pneumonitis. Four of 11 evaluable patients achieved partial responses; all four had non-small-cell lung cancer (NSCLC). The peak plasma concentration of erlotinib, and the area under the concentration-time curve increased proportionally to the dose, suggesting linear PK.
The recommended dose of erlotinib in Japanese patients is 150 mg/day. Further trials in Japanese NSCLC patients are warranted.
本项厄洛替尼I期剂量探索研究的目的是调查毒性特征，确认每日剂量达150mg时的可接受毒性，并评估日本实体瘤患者的药代动力学（PK）特征和抗肿瘤活性。
纳入不适合标准治疗形式的实体瘤患者。第1个治疗周期包括第1天单剂量给药，第2天停药，第3 - 23天每日持续给药，以及第24 - 30天停药。后续周期（28天）采用每日持续给药。厄洛替尼剂量以50mg的增量从50mg/天逐步递增至150mg/天。在第1周期对所有患者进行PK评估。
纳入了15例年龄在38 - 70岁（中位年龄57岁）的患者，其中非小细胞肺癌患者11例、结直肠癌患者3例、头颈癌患者1例。主要毒性为皮疹、腹泻和肝功能障碍，一般程度较轻且易于处理。确认了厄洛替尼在高达150mg/天剂量时具有良好的耐受性。1例患者发生5级治疗相关间质性肺炎。11例可评估患者中有4例获得部分缓解；这4例均为非小细胞肺癌（NSCLC）患者。厄洛替尼的血浆峰浓度以及浓度 - 时间曲线下面积与剂量成比例增加，提示PK呈线性。
日本患者中厄洛替尼的推荐剂量为150mg/天。有必要在日本NSCLC患者中开展进一步试验。
