A Phase I clinical trial has indicated that the combination of upamostat and gemcitabine is well-tolerated in patients with advanced pancreatic cancer. 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 (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 (100, 200, 400, or 600 mg) daily for 28 days, combined with 1000 mg/m² of gemcitabine 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 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.
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 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 (LH011) is an oral prodrug of the serine protease inhibitor WX-UK1, targeting the urokinase-type plasminogen activator (uPA) 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 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 may represent the optimal dose when combined with gemcitabine. Further studies are warranted to evaluate the impact of uPA expression levels on treatment response and to explore the potential of biomarkers like D-dimer as indicators of treatment response and disease progression.
