Ikeda Masafumi, Okusaka Takuji, Mitsunaga Shuichi, Ueno Hideki, Tamai Toshiyuki, Suzuki Takuya, Hayato Seiichi, Kadowaki Tadashi, Okita Kiwamu, Kumada Hiromitsu
National Cancer Center Hospital East, Chiba, Japan.
National Cancer Center Hospital, Tokyo, Japan.
Clin Cancer Res. 2016 Mar 15;22(6):1385-94. doi: 10.1158/1078-0432.CCR-15-1354. Epub 2015 Oct 23.
To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC).
This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child-Pugh (CP) scores: CP-A (score, 5-6) and CP-B (score, 7-8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with ≤ 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients.
In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (C24 h) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but C24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit(+) cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients.
Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A.
确定乐伐替尼在晚期肝细胞癌（HCC）患者中的最大耐受剂量（MTD）、安全性、药代动力学、药效学及初步疗效。
本多中心、开放标签的I期剂量递增研究纳入了年龄在20至80岁、对标准治疗无效且根据Child-Pugh（CP）评分进行肝功能分层的患者：CP-A（评分，5 - 6）和CP-B（评分，7 - 8）。乐伐替尼持续每日给药一次，为期4周的周期。MTD定义为在6例患者的第1周期中出现≤1例剂量限制性毒性（DLT）的最大剂量。
共纳入20例患者（CP-A组9例，CP-B组11例）。CP-A组和CP-B组的MTD分别为每日一次12 mg和8 mg；DLT包括蛋白尿、肝性脑病和高胆红素血症。最常见的3级毒性在CP-A组为高血压，在CP-B组为高胆红素血症。与先前I期研究中其他实体瘤患者相比，HCC患者每日一次12 mg乐伐替尼给药后24小时的血浆浓度（C24 h）更高，但每日一次25 mg乐伐替尼的C24 h相当。乐伐替尼治疗后，循环内皮细胞和c-Kit(+)细胞数量减少，白细胞介素（IL）-6、IL10、粒细胞集落刺激因子和血管内皮生长因子水平升高（P < 0.05）。3例患者出现部分缓解，14例患者肿瘤缩小。
乐伐替尼（每日一次12 mg）显示出初步疗效且毒性可控，是HCC和CP-A患者II期研究的推荐剂量。
