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

• Published in: British journal of cancer Vol. 108; no. 4; pp. 766 - 770
• Main Authors: HEINEMANN, V, EBERT, M. P, LAUBENDER, R. P, BEVAN, P, MALA, C, BOECK, S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 05.03.2013
• Subjects: Adenocarcinoma - drug therapy; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Blood Proteins - administration & dosage; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Drug Administration Schedule; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Middle Aged; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Piperazines - administration & dosage; Short Communication; Sulfonamides - administration & dosage; Tumors; Antineoplastic agent; u-Plasminogen activator; Gemcitabine; Randomization; pancreatic cancer; Cancerology; uPA inhibitor; Pancreas cancer; Phase II trial; Pyrimidine nucleoside; Pancreatic disease; Human; Drug combination; Serine endopeptidases; Enzyme; Malignant tumor; Peptidases; Antimetabolic; Upamostat; Pyrimidine derivatives; Hydrolases; Digestive diseases; Inhibitor; Locally advanced stage; Fluorine Organic compounds; Comparative study; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.62

To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC). 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). 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. 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.