Phase 1 trial of HR070803 (an Irinotecan liposome) in combination with 5-fluorouracil, leucovorin, and oxaliplatin for untreated advanced or metastatic pancreatic ductal adenocarcinoma.

IF 7 1区医学 Q1 MEDICINE, GENERAL & INTERNAL

BMC Medicine Pub Date : 2025-07-07 DOI:10.1186/s12916-025-04234-4

Qiang Xu, Xue Zhao, Xianze Wang, Ruizhe Zhu, Yuejuan Cheng, Tao Xia, Heshui Wu, He Tian, Yuping Sun, Mingjun Zhang, Chuntao Gao, Deliang Fu, Xiaojie Wu, Tongsen Zheng, Xiaoyu Yin, Yili Chen, Xiaobing Chen, Zhihua Li, Rufu Chen, Xue Yang, Huan Wang, Quanren Wang, Xiaohong Han, Wenming Wu

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引用次数: 0

Abstract

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/m² plus 5-FU/LV and oxaliplatin 60 mg/m²) 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/m² plus 5-FU/LV and oxaliplatin 85 mg/m² was chosen as the RP2D.

Trial registration: Clinical trials.gov NCT04796948; registered March 15, 2021.

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HR070803（一种伊立替康脂体）联合5-氟尿嘧啶、亚叶酸蛋白和奥沙利铂治疗未治疗的晚期或转移性胰腺导管腺癌的一期试验。

背景：本研究评估了HR070803（一种新型伊立替康脂体）联合5-FU/LV和奥沙利铂治疗无法切除的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18-70岁的未接受治疗的局部晚期或转移性PDAC患者。治疗剂量从40/60 （HR070803 40 mg/m2 + 5-FU/LV和奥沙利铂60 mg/m2）增加到60/60和60/85。主要终点是最大耐受剂量（MTD）和推荐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：共入组41例患者，其中40/60组6例，60/60组17例，60/85组18例。60/60组中仅有1例出现丙氨酸转氨酶3级升高和天冬氨酸转氨酶3级升高的剂量限制性毒性，未达到MTD。31例（75.6%）患者报告了≥3级的不良事件，最常见的是中性粒细胞计数减少和γ -谷氨酰转移酶升高。没有因不良事件而中断治疗，也没有与治疗相关的死亡。总体缓解（完全或部分缓解）率为29.3%。药代动力学结果显示游离伊立替康循环延长，释放缓慢。结论：HR070803联合5-FU/LV和奥沙利铂具有可接受的毒性、良好的抗肿瘤活性和良好的药代动力学特征，可作为不可切除的局部晚期或转移性PDAC患者的一线治疗。根据剂量升级和剂量扩展阶段获得的综合数据，选择HR070803 60 mg/m2 + 5-FU/LV和奥沙利铂85 mg/m2作为RP2D。试验注册：Clinical trials.gov NCT04796948；于2021年3月15日注册。

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来源期刊

BMC Medicine 医学-医学：内科

CiteScore

13.10

自引率

1.10%

发文量

435

审稿时长

4-8 weeks

期刊介绍： BMC Medicine is an open access, transparent peer-reviewed general medical journal. It is the flagship journal of the BMC series and publishes outstanding and influential research in various areas including clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. In addition to research articles, the journal also publishes stimulating debates, reviews, unique forum articles, and concise tutorials. All articles published in BMC Medicine are included in various databases such as Biological Abstracts, BIOSIS, CAS, Citebase, Current contents, DOAJ, Embase, MEDLINE, PubMed, Science Citation Index Expanded, OAIster, SCImago, Scopus, SOCOLAR, and Zetoc.