Phase I clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer
Phase I clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer
复制标题
DOI：
10.1007/s10637-009-9321-x
复制
发表时间：
2010-12-01
影响因子：
3.4
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Okamoto, Isamu;Miyazaki, Masaki;Nakagawa, Kazuhiko
目前晚期肺癌的治疗效果不理想，促使人们寻找新的治疗方法，多激酶抑制剂索拉非尼是一种候选药物。该I期试验旨在评估索拉非尼联合紫杉醇和卡铂治疗晚期非小细胞肺癌（NSCLC）患者的药物安全性、药代动力学以及肿瘤反应。方法符合条件的患者在第1天接受紫杉醇（200 mg/m(2)）和卡铂（曲线下面积[AUC]为6 mg min mL(-1)），在21天周期的第2至19天接受索拉非尼（400 mg，每日2次）。结果最初的6例患者（队列1）中有4例出现剂量限制性毒性（dlt），导致治疗方案的修改。另外7例患者（队列2）入组，其中2例发展为dlt。DLTs包括队列1中的多形性红斑、手足皮肤反应和血浆丙氨酸转氨酶升高，以及队列2中的转移部位胃肠道穿孔和肺炎。大多数不良事件是可控的。在12例可评估的患者中，观察到1例完全缓解和6例部分缓解。三种药物共同给药对各自的药代动力学没有影响。结论本研究证实索拉非尼400mg每日1次联合卡铂AUC 5mg min mL（-1）和紫杉醇200mg /m(2)治疗日本晚期NSCLC患者是可行的。本研究结果还表明，这种联合治疗在日本NSCLC患者中具有令人鼓舞的抗肿瘤活性，并且与相关的药代动力学相互作用无关。
Objectives Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods Eligible patients received paclitaxel (200 mg/m(2)) and carboplatin (area under the curve [AUC]of 6 mg min mL(-1)) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle. Results Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics. Conclusion The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL(-1) and paclitaxel 200 mg/m(2) is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.