Phase I Clinical Study of the Angiogenesis Inhibitor TSU-68 Combined with Carboplatin and Paclitaxel in Chemotherapy-Naive Patients with Advanced Non-small Cell Lung Cancer
Phase I Clinical Study of the Angiogenesis Inhibitor TSU-68 Combined with Carboplatin and Paclitaxel in Chemotherapy-Naive Patients with Advanced Non-small Cell Lung Cancer
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DOI：
10.1097/jto.0b013e318238154d
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发表时间：
2012-02-01
影响因子：
20.4
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Okamoto, Isamu;Yoshioka, Hiroshige;Nakagawa, Kazuhiko
简介：大津-68是一种口服小分子抑制剂，靶向血管内皮生长因子受体2、血小板衍生生长因子受体β和成纤维细胞生长因子受体1。进行开放标签、单臂、I期研究以评估递增剂量的TSU-68联合标准化疗治疗晚期非小细胞肺癌患者。方法：符合条件的患者接受TSU-68，200或400 mg，每日两次，并连续联合卡铂（曲线下面积，6 mg。结果：37例患者接受了大津-68的两个剂量水平治疗。在200 mg每日两次剂量水平下，未观察到大津-68的剂量限制性毒性。在400 mg每日两次时，6名患者中有1名在第一个周期内发生了剂量限制性毒性（3级厌食）。400 mg每日两次剂量水平被确定为推荐剂量，共有34例患者接受了该剂量治疗。总体而言，不良事件的严重程度为轻度至中度，最常见的此类事件为骨髓抑制、神经病变和胃肠道疾病。未观察到药物相关出血。客观缓解率为39.4%（95%置信区间，22.9 - 57.9%），中位无进展生存期为5.6个月（95%置信区间，3.6 - 7.2个月）。共同管理的大津-68，卡铂，紫杉醇对这些药物的药代动力学没有实质性的影响。结论：大津-68可以安全地与标准剂量的卡铂-紫杉醇，与组合表现出有前途的抗肿瘤活性。
Introduction: TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor beta, and fibroblast growth factor receptor 1. An open-label, single-arm, phase I study was performed to evaluate escalating doses of TSU-68 in combination with standard chemotherapy in patients with advanced non-small cell lung cancer.Methods: Eligible patients received TSU-68 at 200 or 400 mg twice daily and continuously in combination with carboplatin (area under the curve, 6mg . min/mL) plus paclitaxel (200 mg/m(2)) on day 1 every 21 days.Results: Thirty-seven patients were enrolled at the two dose levels of TSU-68. No dose-limiting toxicities were observed with TSU-68 at the 200 mg twice a day dose level. At 400 mg twice a day, one of six patients experienced a dose-limiting toxicity (anorexia of grade 3) during the first cycle. The 400 mg twice a day dose level was determined to be the recommended dose, and a total of 34 patients were treated at this dose. Overall, adverse events were mild to moderate in severity, with the most frequently observed such events being myelosuppression, neuropathy, and gastrointestinal disorders. No drug-related bleeding was observed. The objective response rate was 39.4% (95% confidence interval, 22.9-57.9%), and median progression-free survival was 5.6 months (95% confidence interval, 3.6-7.2 months). Coadministration of TSU-68, carboplatin, and paclitaxel had no substantial impact on the pharmacokinetics of these drugs.Conclusions: TSU-68 can be safely combined with standard doses of carboplatin-paclitaxel, with the combination manifesting promising antitumor activity.