一项评估增加剂量的S-1联合奥沙利铂和纳武单抗用于HER2阴性晚期胃癌安全性的I/II期试验。
A phase I/II trial evaluating the safety of increased-dose S- 1 with oxaliplatin and nivolumab in HER2-negative advanced gastric cancer.
作者信息
Baba Keisuke, Suzuki Nobumi, Imamura Chiyo K, Booka Eisuke, Takeuchi Masashi, Takahari Daisuke, Kawakami Takeshi, Kawakubo Hirofumi, Kitagawa Chiyoe, Kono Yoshiyasu, Ogura Keiji, Kito Yosuke, Saito Kei, Yamamoto Shinzo, Takeuchi Hiroya, Kudo Toshihiro, Tsunoda Takuya, Mizukami Takuro, Yamaguchi Toshifumi, Shoji Hirokazu, Saito Kanako, Tanoue Kenro, Baba Eishi, Nagashima Kengo, Boku Narikazu
机构信息
Department of Oncology and General Medicine, IMSUT Hospital, the Institute of Medical Science Hospital, the University of Tokyo, Tokyo, Japan.
Department of Gastroenterology Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
出版信息
BMC Cancer. 2025 Apr 12;25(1):675. doi: 10.1186/s12885-025-14084-1.
BACKGROUND
We developed and refined an S-1 dosage formula based on renal function, sex, and body surface area (BSA) to achieve the target area under the concentration-time curve of 5-fluorouracil in two prospective pharmacokinetic studies. The clinical validity of the refined formula (BBT formula) was evaluated using data from the two phase III trials of fist-line chemotherapy including S-1 for advanced gastric cancer, which demonstrated that overall survival and progression-free survival tended to be shorter in patients whose S-1 standard dose, based on BSA alone, was lower than that determined using the BBT formula.
METHODS
Chemo-naïve patients with HER2-negative advanced gastric or gastroesophageal junction cancer, whose standard S-1 dose is lower than that determined using the BBT formula, receive S-1 at an increased dose based on the BBT formula plus oxaliplatin (130 mg/m) and nivolumab (360 mg/body). The primary endpoint is the incidence of dose-limiting toxicity in six patients in the phase I part and the proportion of patients requiring S-1 dose reduction in a total of 20 patients, expecting 30% and rejecting 50% with an alpha error of 0.1 and beta error of 0.2. The secondary endpoints are adverse events, relative dose intensity, response rate, disease control rate, progression-free survival, and overall survival. A correlation study is conducted to investigate the immune profiles associated with efficacy.
DISCUSSION
This phase I/II trial evaluates the safety and efficacy of S-1 at increased doses, determined by the BBT formula, in combination with oxaliplatin and nivolumab in patients with HER2-negative advanced gastric cancer, whose standard dose of S- 1 is lower than the dose recommended dose by the BBT formula.
TRIAL REGISTRATION
This study was approved by the University of Tokyo Clinical Research Review Board (URL: https://www.ut-crescent.jp/patients/chiken_jisshi/ , review number: 2022529SP) and was initiated at 19 institutions in June 2023 (registered as jRCTs031230127).
背景
在两项前瞻性药代动力学研究中，我们基于肾功能、性别和体表面积（BSA）制定并完善了S-1剂量公式，以实现5-氟尿嘧啶浓度-时间曲线下的目标面积。使用两项一线化疗III期试验的数据评估了完善后的公式（BBT公式）的临床有效性，这两项试验包括用于晚期胃癌的S-1，结果表明，仅基于BSA的S-1标准剂量低于使用BBT公式确定剂量的患者，其总生存期和无进展生存期往往更短。
方法
既往未接受过化疗的HER2阴性晚期胃癌或胃食管交界癌患者，其标准S-1剂量低于使用BBT公式确定的剂量，基于BBT公式增加S-1剂量，并联合奥沙利铂（130mg/m²）和纳武利尤单抗（360mg/体）。主要终点是I期部分6例患者中剂量限制毒性的发生率以及总共20例患者中需要降低S-1剂量的患者比例，预期发生率为30%，拒绝率为50%，α错误为0.1，β错误为0.2。次要终点是不良事件、相对剂量强度、缓解率、疾病控制率、无进展生存期和总生存期。进行相关性研究以调查与疗效相关的免疫谱。
讨论
这项I/II期试验评估了在HER2阴性晚期胃癌患者中，由BBT公式确定的增加剂量的S-1联合奥沙利铂和纳武利尤单抗的安全性和有效性，这些患者的S-1标准剂量低于BBT公式推荐剂量。
试验注册
本研究经东京大学临床研究审查委员会批准（网址：https://www.ut-crescent.jp/patients/chiken_jisshi/，审查编号：2022529SP），并于2023年6月在19个机构启动（注册为jRCTs031230127）。
Zotero 插件