Background: Biliary cancers (BC) have no clear second-line therapy in advanced disease after progression on standard of care gemcitabine and cisplatin. Angiogenesis has been shown to be a potential target for BC, and ramucirumab, FDA-approved for treatment of advanced gastric, lung and colon cancer, is a novel monoclonal antibody that targets VEGFR2 to inhibit tumor-induced angiogenesis. Methods: We conducted a single arm, phase 2 single center study. Eligibility criteria included patients (pts) with advanced BC, ECOG PS 0 or 1, who had received at least 1 prior regimen containing gemcitabine. Pts were treated with IV ramucirumab at a dose of 8 mg/kg every 2 weeks, and restaging imaging was performed every 8 weeks until progression. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS) and toxicity (tox) of ramucirumab. Exploratory endpoints included correlating baseline gene expression profile and pre- and post-therapy CT imaging features with tumor response. Results: 43 of a planned 50 pts were enrolled, 42 receiving treatment. The cohort had a median age of 59.9 yrs (range 42-77), ECOG PS 0/1 (16/26), male/female (20/22), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (23/9/10), median prior therapies = 1 (range 1 to 5). Pts received a median number of 6 cycles. There were 9 (21%) grade 3 tox including anorexia, dehydration, hypertension, hyponatremia, proteinuria and vomiting. No grade 4 tox were observed, and no pts were taken off study due to tox. 5 pts required dose reductions. After a median follow-up of 3.44 months, the median PFS and OS were 2.73 months (95% CI: 1.91-8.03) and 6.31 months (95% CI: 4.7 – not reached). Of 34 pts evaluable for response, ORR = 0% and DCR = 44%, with 6 pts on treatment for > 24 weeks. Analysis of the correlative endpoints is ongoing. Conclusions: Ramucirumab as a single agent was well-tolerated and resulted in a PFS similar to that achieved with more toxic chemotherapy regimens used in the refractory setting. Furthermore, a minority of ramucirumab-treated patients (13%) experienced prolonged PFS > 24 weeks, warranting further investigation of this agent in refractory BC. Clinical trial information: NCT02520141