A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer

Abstract

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.

Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis

“…Combination chemotherapy using nafamostat mesilate and oxaliplatin induces synergistic cytotoxicity in pancreatic cancer [35]. Importantly, the median survival time of patients treated with gemcitabine plus intra-arterial nafamostat mesilate was approximately two months longer than that with the gemcitabine alone without adverse effects as demonstrated in a phase Ι study of unresectable pancreatic cancer [36]. We therefore conceptualized that both de novo and acquired resistance to therapy could be attenuated using combination therapy based on sound rationale and hypothesized that nafamostat mesilate may be a novel chemosensitizing agent.…”

Effect of NF-κB inhibition on chemoresistance in biliary–pancreatic cancer

“…We applied nafamostat mesilate a NF-κB inhibitor in our phase I and phase II studies. As the concentration of nafamostat mesilate under conditions of continuous intravenous infusion was insufficient to inhibit NF-κB activation, regional arterial infusion using a port-catheter system was selected [56]. Although the development of novel drugs for biliary-pancreatic cancer is needed, physicians currently have no choice but to use existing agents.…”

“…In that study, the median survival time achieved with the combination chemotherapy in the patients with gemcitabine-resistant pancreatic cancer was 161 days (95 % confidence interval 109-223 days), and the 1-year survival rate was 19 % [55]. Chemotherapy with nafamostat mesilate and gemcitabine was administered for locally advanced or metastatic pancreatic cancer in a phase I (n = 12) and phase II study (n = 35) [56,57]. The median survival time was 10 months (95 % confidence interval 9.3-13.5 months), with a 1-year survival rate of 40 % [57], while the response and disease control rates were 17.1 and 88.6 %, respectively.…”

“…The safety of repeated-dose administration of Combination Nafamostat mesilate/Gemcitabine Phase I Uwagawa et al [55] Nafamostat mesilate/Gemcitabine Phase II Uwagawa et al [56] Isoflavones/Erlotinib/Gemcitabine Phase II El-Rayes et al [57] Curcumin/Gemcitabine Phase I/II Kanai et al [54] Bortezomib/Paclitaxel Phase I Ramaswamy et al [58] Bortezomib/Irinotecan Phase I Ryan et al [59] Bortezomib/Gemcitabine Phase II Alberts et al [60] Thalidomide/Gemcitabine Phase II Maples et al [61] Lenalidomide/Gemcitabine Phase II Infante et al [62] Pomalidomide/Gemcitabine Phase I Infante et al [63] Thalidomide/Capecitabine Phase II Shi et al [64] Biliary Monotherapy Curcumin Phase I Kanai et al [65] Theracurmin ® containing 200 mg of curcumin under combination treatment with gemcitabine-based chemotherapy was assessed for standard chemotherapy-resistant pancreatic or biliary tract cancer (n = 16) [66].…”

Anti-tumor effect by inhibition of NF-κB activation using nafamostat mesilate for pancreatic cancer in a mouse model

“…We have reported that nafamostat mesilate inhibits NF-κB activation by suppressing IκB· phosphorylation and induces caspase-8 mediated apoptosis of pancreatic cancer cells (16). Also, high efficacy of nafamostat mesilate combined with gemcitabine for pancreatic cancer has been demonstrated in animal experiments (17) that applied to clinical trials (18). Nafamostat mesilate, which is a serine-protease inhibitor (19,20), is widely used for treatment of pancreatitis (21), disseminated intravascular coagulation (22), and anticoagulation in hemodialysis (23) in Japan, and has only minimal adverse effects such as hyperkalemia or hyponatremia (24)(25)(26).…”