Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer

BACKGROUND: To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Within a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m(−2) of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included response rate, time to first metastasis, progression-free and overall survival (OS). RESULTS: Of the 95 enroled patients, 85 were evaluable for response and 93 for safety. Median OS was 12.5 months (95% CI 8.2–18.2) in arm C, 9.7 months (95% CI 8.4–17.1) in arm B and 9.9 months (95% CI 7.4–12.1) in arm A; corresponding 1-year survival rates were 50.6%, 40.7% and 33.9%, respectively. More patients achieved a partial remission (confirmed responses by RECIST) with upamostat combination therapy (arm C: 12.9% arm B: 7.1% arm A: 3.8%). Overall, only 12 patients progressed by developing detectable distant metastasis (arm A: 4, arm B: 6, arm C: 2). The most common adverse events considered to be related to upamostat were asthenia, fever and nausea. CONCLUSION: In this proof-of-concept study targeting the uPA system in LAPC, the addition of upamostat to gemcitabine was tolerated well; similar survival results were observed for the three treatment arms.