HR070803（一种伊立替康脂质体）联合5-氟尿嘧啶、亚叶酸钙和奥沙利铂用于未经治疗的晚期或转移性胰腺导管腺癌的1期试验。
Phase 1 trial of HR070803 (an Irinotecan liposome) in combination with 5-fluorouracil, leucovorin, and oxaliplatin for untreated advanced or metastatic pancreatic ductal adenocarcinoma.
作者信息
Xu Qiang, Zhao Xue, Wang Xianze, Zhu Ruizhe, Cheng Yuejuan, Xia Tao, Wu Heshui, Tian He, Sun Yuping, Zhang Mingjun, Gao Chuntao, Fu Deliang, Wu Xiaojie, Zheng Tongsen, Yin Xiaoyu, Chen Yili, Chen Xiaobing, Li Zhihua, Chen Rufu, Yang Xue, Wang Huan, Wang Quanren, Han Xiaohong, Wu Wenming
机构信息
General Surgery Department, Dongcheng District, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China.
Clinical Pharmacology Research Centre, Dongcheng District, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China.
出版信息
BMC Med. 2025 Jul 7;23(1):402. doi: 10.1186/s12916-025-04234-4.
BACKGROUND
This study assessed the safety, preliminary antitumor activity, and pharmacokinetics of HR070803 (a novel liposomal irinotecan) in combination with 5-FU/LV and oxaliplatin for treatment-naive patients with unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).
METHODS
This multicenter, open-label, single-arm, dose-escalation phase 1 study recruited treatment-naive patients aged 18-70 years with unresectable locally advanced or metastatic PDAC. Treatment doses were escalated from 40/60 (HR070803 40 mg/m plus 5-FU/LV and oxaliplatin 60 mg/m) to 60/60 and 60/85. The primary endpoints were maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary endpoints included safety, preliminary antitumor activity, and pharmacokinetics.
RESULTS
A total of 41 patients were enrolled, including 6, 17, and 18 patients in the 40/60, 60/60, and 60/85 group, respectively. Only one patient in the 60/60 group experienced dose-limiting toxicities of grade 3 increased alanine aminotransferase and grade 3 increased aspartate aminotransferase, and the MTD was not reached. Adverse events of grade ≥ 3 were reported in 31 (75.6%) patients, with the most common being decreased neutrophil count and increased gamma-glutamyltransferase. No treatment discontinuation occurred owing to adverse events, and there were no treatment-related deaths. The overall response (complete or partial response) rate was 29.3% in the total population. Pharmacokinetic results demonstrated prolonged circulation and slow release of free irinotecan.
CONCLUSIONS
HR070803 plus 5-FU/LV and oxaliplatin demonstrated an acceptable toxicity, good antitumor activity, and favorable pharmacokinetic profile as a first-line treatment for patients with unresectable locally advanced or metastatic PDAC. Based on the comprehensive data obtained during the dose escalation and dose expansion stages, HR070803 60 mg/m plus 5-FU/LV and oxaliplatin 85 mg/m was chosen as the RP2D.
TRIAL REGISTRATION
Clinical trials.gov NCT04796948; registered March 15, 2021.
背景
本研究评估了HR070803（一种新型脂质体伊立替康）联合5-氟尿嘧啶/亚叶酸钙和奥沙利铂用于未经治疗的不可切除局部晚期或转移性胰腺导管腺癌（PDAC）患者的安全性、初步抗肿瘤活性和药代动力学。
方法
这项多中心、开放标签、单臂、剂量递增的1期研究招募了年龄在18-70岁、未经治疗的不可切除局部晚期或转移性PDAC患者。治疗剂量从40/60（HR070803 40mg/m²加5-氟尿嘧啶/亚叶酸钙和奥沙利铂60mg/m²）逐步递增至60/60和60/85。主要终点是最大耐受剂量（MTD）和推荐的2期剂量（RP2D）。次要终点包括安全性、初步抗肿瘤活性和药代动力学。
结果
共纳入41例患者，40/60组、60/60组和60/85组分别有6例、17例和18例患者。60/60组中仅1例患者出现3级丙氨酸转氨酶升高和3级天冬氨酸转氨酶升高的剂量限制性毒性，未达到MTD。31例（75.6%）患者报告了≥3级不良事件，最常见的是中性粒细胞计数减少和γ-谷氨酰转移酶升高。未因不良事件导致治疗中断，也没有与治疗相关的死亡。总人群的总体缓解（完全或部分缓解）率为29.3%。药代动力学结果表明游离伊立替康的循环时间延长且释放缓慢。
结论
HR070803联合5-氟尿嘧啶/亚叶酸钙和奥沙利铂作为不可切除局部晚期或转移性PDAC患者的一线治疗方案，显示出可接受的毒性、良好的抗肿瘤活性和有利的药代动力学特征。基于剂量递增和剂量扩展阶段获得的综合数据，选择HR070803 60mg/m²加5-氟尿嘧啶/亚叶酸钙和奥沙利铂85mg/m²作为RP2D。
试验注册
ClinicalTrials.gov NCT04796948；于2021年3月15日注册。
Zotero 插件