Upamostat Plus Gemcitabine Shows Tolerability in Advanced Pancreatic Cancer Phase I Trial

A Phase I clinical trial has indicated that the combination of upamostat查看药品详情 and gemcitabine查看药品详情 is well-tolerated in patients with advanced pancreatic cancer (搜索)搜索该疾病. The study, designed to assess the maximum tolerated dose (MTD) of upamostat when combined with gemcitabine, also provided initial insights into the efficacy of this combination in treating advanced pancreatic ductal adenocarcinoma (搜索)搜索该疾病 (PDAC). The trial enrolled patients with locally advanced unresectable or metastatic pancreatic cancer.

Study Design and Patient Population

The nonrandomized, single-arm, dose-escalation trial enrolled 17 patients between May 2020 and November 2022. Participants received escalating doses of oral upamostat查看药品详情 (100, 200, 400, or 600 mg) daily for 28 days, combined with 1000 mg/m² of gemcitabine查看药品详情 on days 8 and 15 of the first cycle, and days 1 and 8 of subsequent cycles. Key inclusion criteria included histologically confirmed pancreatic adenocarcinoma, age between 18 and 75 years, ECOG performance status of 0-2, and adequate organ function. The primary endpoint was to determine the MTD of upamostat in combination with gemcitabine.

Safety and Tolerability

The trial found that no dose-limiting toxicities (DLTs) were observed at upamostat查看药品详情 doses of 100, 200, or 400 mg once daily. Although three serious adverse events (SAEs) occurred at the 100 and 200 mg doses, these occurred outside the DLT observation period. Escalation to 600 mg also did not result in DLTs, and the MTD was not reached. Treatment-related adverse events (AEs) were observed in all patients, with the most common being hematological, including leucopenia, neutropenia, thrombocytopenia, and anemia. Other AEs included nausea, vomiting, diarrhea, and constipation. Notably, sinus bradycardia was possibly linked to upamostat rather than gemcitabine查看药品详情.

Efficacy and Pharmacokinetics

While tumor response did not significantly differ among the dose groups, 12 patients (70.6%) experienced stable disease (SD) during the main research period (days 0-49). Four patients (23.5%) experienced progressive disease (PD), and one patient withdrew due to a SAE. Nine patients (52.9%) experienced tumor shrinkage. Pharmacokinetic analysis revealed a dose-related increase in upamostat查看药品详情 and its metabolite WX-UK1 exposure from 100 to 400 mg, but not in the 600 mg group. The average progression-free survival (PFS) was 100 days, with one patient achieving partial response (PR) after 4 cycles and another reaching a PFS of 369 days.

Mechanism of Action and Clinical Context

Upamostat查看药品详情 (LH011) is an oral prodrug of the serine protease inhibitor WX-UK1, targeting the urokinase-type plasminogen activator (uPA (搜索)搜索该靶点) system, which plays a crucial role in tumor invasiveness and metastasis. Elevated levels of uPA are associated with poorer survival outcomes in advanced PDAC patients. Gemcitabine查看药品详情 remains a cornerstone of chemotherapy regimens for advanced PDAC, but its efficacy is limited, necessitating the development of more effective treatment options. The combination of upamostat and gemcitabine aims to enhance the efficacy of gemcitabine-based treatments by inhibiting the uPA system.

Optimal Dosing Considerations

Based on the pharmacokinetic and safety data, investigators suggest that either 200 mg or 400 mg of upamostat查看药品详情 may represent the optimal dose when combined with gemcitabine查看药品详情. Further studies are warranted to evaluate the impact of uPA (搜索)搜索该靶点 expression levels on treatment response and to explore the potential of biomarkers like D-dimer as indicators of treatment response and disease progression.