一项关于S-1联合索拉非尼治疗晚期肝细胞癌患者的I/II期研究。
A phase I/II study of S-1 with sorafenib in patients with advanced hepatocellular carcinoma.
作者信息
Ooka Yoshihiko, Chiba Tetsuhiro, Ogasawara Sadahisa, Arai Kuniaki, Suzuki Eiichiro, Tawada Akinobu, Yamashita Tatsuya, Kanai Fumihiko, Kaneko Shuichi, Yokosuka Osamu
机构信息
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
出版信息
Invest New Drugs. 2014 Aug;32(4):723-8. doi: 10.1007/s10637-014-0077-6. Epub 2014 Mar 7.
BACKGROUND
Sorafenib is the sole molecular-targeted agent showing a survival benefit in patients with advanced hepatocellular carcinoma (HCC). We evaluated the tolerability and effectiveness of a combination of S-1 with sorafenib in patients with advanced HCC.
METHODS
S-1 was administered during days 1-14 and sorafenib was administered every day. This treatment was repeated every 21 days. In phase I, we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The dose of each drug was planned as follows: cohort 1: S-1 48 mg/m(2)/day and sorafenib 400 mg/day, cohort 2a: S-1 48 mg/m(2)/day and sorafenib 800 mg/day, cohort 2b: S-1 64 mg/m(2)/day and sorafenib 400 mg/day, cohort 3: S-1 64 mg/m(2)/day and sorafenib 800 mg/day, and cohort 4: S-1 80 mg/m(2)/day and sorafenib 800 mg/day. In phase II, the patients were treated at the MTD to evaluate safety and efficacy.
RESULTS
Nineteen patients were enrolled in phase I. One of the six patients in cohort 1 and one of the six patients in cohort 3 experienced DLT. None of the three patients in cohort 2a experienced DLT and three of the four patients in cohort 4 experienced DLT. Therefore, cohort 3 was considered the MTD. Subsequently, 26 patients were enrolled in phase II. The most common grade 3/4 toxicities were an increase of aspartate aminotransferase (38.5 %), thrombocytopenia (23.1 %), neutropenia (19.2 %), hyperbilirubinemia (15.4 %), an increase of alanine aminotransferase (15.4 %), hyponatremia (11.5 %), rash (11.5 %), and hypophosphatemia (11.5 %). Sudden death occurred in one patient (3.8 %). A patient (3.8 %) had a partial response, 15 (57.7 %) had stable disease, and 10 (38.5 %) had progressive disease. The median times to progression and overall survival were 2.4 and 10.5 months, respectively.
CONCLUSION
The MTD of S-1 and sorafenib in patients with advanced HCC was 64 mg/m(2)/day and 800 mg/day, respectively. This dose/regimen demonstrated substantial clinical activity among patients with advanced HCC.
背景
索拉非尼是唯一一种对晚期肝细胞癌（HCC）患者有生存获益的分子靶向药物。我们评估了S-1联合索拉非尼治疗晚期HCC患者的耐受性和有效性。
方法
S-1在第1 - 14天给药，索拉非尼每日给药。每21天重复此治疗。在I期，我们确定了最大耐受剂量（MTD）和剂量限制性毒性（DLT）。每种药物的剂量计划如下：队列1：S-1 48 mg/m²/天，索拉非尼400 mg/天；队列2a：S-1 48 mg/m²/天，索拉非尼800 mg/天；队列2b：S-1 64 mg/m²/天，索拉非尼400 mg/天；队列3：S-1 64 mg/m²/天，索拉非尼800 mg/天；队列4：S-1 80 mg/m²/天，索拉非尼800 mg/天。在II期，患者按MTD治疗以评估安全性和有效性。
结果
19例患者入组I期。队列1的6例患者中有1例、队列3的6例患者中有1例发生DLT。队列2a的3例患者均未发生DLT，队列4的4例患者中有3例发生DLT。因此，队列3被认为是MTD。随后，26例患者入组II期。最常见的3/4级毒性反应为天冬氨酸转氨酶升高（38.5%）、血小板减少（23.1%）、中性粒细胞减少（19.2%）、高胆红素血症（15.4%）、丙氨酸转氨酶升高（15.4%）、低钠血症（11.5%）、皮疹（11.5%）和低磷血症（11.5%）。1例患者（3.8%）猝死。1例患者（3.8%）部分缓解，15例（57.7%）病情稳定，10例（38.5%）病情进展。进展时间和总生存时间的中位数分别为2.4个月和10.5个月。
结论
晚期HCC患者中S-1和索拉非尼的MTD分别为64 mg/m²/天和800 mg/天。该剂量/方案在晚期HCC患者中显示出显著的临床活性。
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