Lai Xiuping, Cheng Di, Xu Huixin, Wang Jingshu, Lv Xiaozhi, Yao Herui, Li Liuning, Wu Junyan, Ye Suiwen, Li Zhihua
Phase I Clinical Trial Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Cancer Med. 2025 Jan;14(1):e70550. doi: 10.1002/cam4.70550.
This study aimed to determine the maximum tolerated dose (MTD) of the urokinase plasminogen activator (uPA) inhibitor upamostat (LH011) in combination with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer.
Seventeen patients were enrolled and received escalating doses of oral LH011 (100, 200, 400, or 600 mg) daily alongside 1000 mg/m of gemcitabine. Safety profiles, tumor response (including response rate and progression-free survival), pharmacokinetics, and changes in CA199 and D-dimer levels were assessed.
During the study period (Day0-Day49), no patients achieved partial response. Stable disease (SD) was observed in 12 patients (70.6%), while four patients (23.5%) experienced progressive disease (PD). One patient withdrew due to a serious adverse event (SAE) on D47. Pharmacokinetic analysis revealed a dose-related increase in LH011 and its metabolite WX-UK1 exposure from 100 to 400 mg but not in the 600 mg group. Hematological toxicity, mainly attributable to gemcitabine, was the predominant grade 3 or 4 adverse event, with additional occurrences of loss of appetite, rash, and interstitial lung disease. Sinus bradycardia possibly linked to LH011 rather than gemcitabine was noted. The MTD was not reached.
Combining LH011 at doses ranging from 100 to 600 mg with gemcitabine every 21 days demonstrated manageable safety and tolerability. However, tumor response did not significantly differ among the dose groups, suggesting the need for further investigation.
NCT05329597.
本研究旨在确定尿激酶型纤溶酶原激活剂（uPA）抑制剂乌帕司他（LH011）与吉西他滨联合用于局部晚期不可切除或转移性胰腺癌的最大耐受剂量（MTD）。
招募了17名患者，每天接受递增剂量的口服LH011（100、200、400或600毫克），同时接受1000毫克/平方米的吉西他滨。评估了安全性、肿瘤反应（包括缓解率和无进展生存期）、药代动力学以及CA199和D - 二聚体水平的变化。
在研究期间（第0天至第49天），没有患者达到部分缓解。12名患者（70.6%）观察到疾病稳定（SD），而4名患者（23.5%）出现疾病进展（PD）。一名患者在第47天因严重不良事件（SAE）退出。药代动力学分析显示，LH011及其代谢物WX - UK1的暴露量在100至400毫克剂量时与剂量相关增加，但在600毫克组中未增加。血液学毒性主要归因于吉西他滨，是主要的3级或4级不良事件，此外还出现了食欲不振、皮疹和间质性肺病。注意到可能与LH011而非吉西他滨相关的窦性心动过缓。未达到MTD。
每21天将100至600毫克剂量的LH011与吉西他滨联合使用显示出可控的安全性和耐受性。然而，各剂量组之间的肿瘤反应没有显著差异，表明需要进一步研究。
NCT05329597。
