Department of Medical Oncology, Department of Oncology, Fudan University Shanghai Cancer Center, Fudan University, No. 273, Dongan Road, Shanghai, 200032, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Invest New Drugs. 2024 Aug;42(4):462-470. doi: 10.1007/s10637-024-01442-2. Epub 2024 Jul 22.
This phase 1b study aimed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of HR070803, a novel nanoliposomal formulation of irinotecan, in combination with 5-fluorouracil and leucovorin in patients with pretreated advanced solid tumors. This study consisted of dose-escalation and expansion stages. Dose escalation was performed with a traditional 3 + 3 design; patients received intravenous infusion of HR070803 from 60 to 80 mg/m, followed by leucovorin (200 mg/m) and 5-fluorouracil (2000 mg/m) every 2 weeks. In the expansion stage, patients received treatments at selected tolerable dose. Fifteen patients received treatments at 60 mg/m (n = 12) and 80 mg/m (n = 3). DLTs occurred in 2 patients at 80 mg/m (grade 2 neutropenia that resulted in a dose delay of ≥ 7 days, n = 1; grade 3 febrile neutropenia, n = 1). The MTD was determined to be 60 mg/m. The most frequent HR070803related adverse events included anorexia, leukopenia, neutropenia, nausea, fatigue, and diarrhea. SN-38, the active metabolite of irinotecan, exhibited lower maximum plasma concentrations and a prolonged terminal half-life when irinotecan was administered via nanoliposome compared to conventional injection. Overall, 4 patients achieved a partial response (confirmed, n = 2), and 9 had stable disease. The MTD of HR070803 was 60 mg/m when infused with 5-fluorouracil and leucovorin. Nanoliposomal encapsulation modified the pharmacokinetics of irinotecan and SN-38. HR070803 with 5-fluorouracil and leucovorin demonstrated a manageable safety profile and promising antitumor efficacy in advanced solid tumors. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05086848. Retrospectively registered on Oct. 12, 2021.
这项 1b 期研究旨在评估 HR070803（一种新型伊立替康纳米脂质体制剂）与氟尿嘧啶和亚叶酸联合用于预处理的晚期实体瘤患者的剂量限制毒性 (DLT)、最大耐受剂量 (MTD)、药代动力学和初步疗效。该研究包括剂量递增和扩展阶段。剂量递增采用传统的 3+3 设计；患者每 2 周接受 HR070803 静脉输注，剂量为 60 至 80mg/m，随后给予亚叶酸（200mg/m）和氟尿嘧啶（2000mg/m）。在扩展阶段，患者接受选定的耐受剂量治疗。15 名患者接受 60mg/m（n=12）和 80mg/m（n=3）的治疗。80mg/m 剂量水平有 2 名患者出现 DLT（2 级中性粒细胞减少症导致剂量延迟≥7 天，n=1；3 级发热性中性粒细胞减少症，n=1）。MTD 确定为 60mg/m。最常见的 HR070803 相关不良事件包括厌食、白细胞减少症、中性粒细胞减少症、恶心、疲劳和腹泻。伊立替康的活性代谢物 SN-38 经纳米脂质体给药时，与传统注射相比，最大血浆浓度较低，终末半衰期延长。总体而言，4 名患者（2 名确认）部分缓解，9 名患者病情稳定。HR070803 与氟尿嘧啶和亚叶酸联合使用时，MTD 为 60mg/m。纳米脂质体包封改变了伊立替康和 SN-38 的药代动力学。HR070803 联合氟尿嘧啶和亚叶酸具有可管理的安全性特征和有前途的晚期实体瘤抗肿瘤疗效。试验注册：Clinicaltrials.gov，NCT05086848。于 2021 年 10 月 12 日回顾性注册。
