Background: Pancreatic cancer cells in vitro undergo epithelial to mesenchymal transformation (EMT) by up-regulating mesenchymal markers, including N-cadherin. The EMT leads to increased motility & invasiveness with collagen exposure in a pancreatic cancer mouse model, which can be inhibited by N-cadherin knockdown. ADH-1 is a small, cyclic pentapeptide with inhibitory effects on stromal & endothelial cells expressing N-cadherin. Methods: Escalating doses of ADH-1 were given twice weekly for 3 wk (1,000, 2,000 & 4,000 mg) with Cisp 25 mg/m²& Gem1000 mg/m²/100 min days 1 & 8 of a 3 wk cycle in pts with pancreaticobiliary cancers with ECOG PS 0-2 & adequate bone marrow, renal & hepatic function. Standard 3 + 3 dose escalation was used. Peripheral blood was collected for biomarkers prior to each dose of ADH-1 during cycle 1. Due to limited drug supply, ADH-1 was given for the 1^st 3 cycles. Results: Between 05/2013 - 04/2015, 17 pts were enrolled, received at least 1 dose of therapy, and were evaluable for toxicity: m 13/F 4; median 60 yr (range 37-81); pancreas 9 /biliary 8. 3 pts had prior adjuvant therapy. The number pts with dose-limiting toxicity during cycle 1 of ADH-1 (mg) were 0/4 at 1,000; 1/7 at 2,000 (gr 4 ANC, platelet); 2/6 pts 4,000 mg (1 pt: gr 3 pulmonary embolus and gr 4 plt; 1: gr 4 cholangitis/sepsis/multiorgan failure). 5 of 8 pts who had ≥ 6 cycles were taken off study due to cumulative toxicities rather than PD. 14 pts had ≥ 3 cycles of therapy and were evaluable for response: SD in 9 subjects; PD in 5. The median number cycles was 5.5 (range 1-30). Median time to treatment failure (TTF) for all patients was 113 days (range 7-724). Median OS was 218 days (7-853+). Pts with biliary cancer had a longer TTF and OS vs pancreatic cancer (TTF 217 vs 93 days; OS 305 vs 180 days). 6 pts survived > 12 months (biliary 4, pancreas 2). Biomarker analysis (ICAM 1; E selectin; VEGF, Soluble VEGF-R 2 and 3, FGF basic) is ongoing. Conclusions: The phase II dose of ADH1 given with Cisp/Gem is 2,000 mg IV twice weekly. ADH-1 was relatively well tolerated. Most pts ultimately required dose delays or reductions due to cumulative toxicity with Cisp/Gem. Clinical trial information: NCT01825603