A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer.
BACKGROUND
The primary end points of this study were to determine the dose-limiting toxic effects (DLTs), maximum tolerated dose, and a recommended phase II dose of a synthetic serine protease inhibitor, nafamostat mesilate, in combination with full-dose gemcitabine in patients with unresectable locally advanced or metastatic pancreatic cancer. The secondary end point was to assess therapeutic response.


PATIENTS AND METHODS
Patients with previously untreated pancreatic cancer received gemcitabine (1 000 mg/m(2) i.v. for 30 min) on days 1, 8, and 15, with nafamostat mesilate (continuous regional arterial infusion for 24 h through a port-catheter system) on days 1, 8, and 15; this regimen was repeated at 28-day intervals. The initial dose of nafamostat mesilate was 2.4 mg/kg and was escalated in increments of 1.2 mg/kg until a dose of 4.8 mg/kg was achieved. A standard '3+3' phase I dose-escalation design was used. Therapeutic response and clinical benefit response were assessed.


RESULTS
Twelve patients were enrolled in this study. None of the patients experienced DLTs, and nafamostat mesilate was well tolerated at doses up to 4.8 mg/kg in combination with full-dose gemcitabine. This combination chemotherapy yielded a reduction of a high serum level of the tumor marker CA19-9. Pain was reduced in three of seven patients without oral morphine sulfate. Overall survival was 7.1 months for all patients.


CONCLUSION
This phase I study was carried out safely. This combination chemotherapy showed beneficial improvement in health-related quality of life. The recommended phase II dose of nafamostat mesilate in combination with full-dose gemcitabine is 4.8 mg/kg.