Background: Currently, there is no standard second line treatment for patients with advanced biliary tract cancer (BC) who have failed prior systemic therapy. Aberrant activation of the Ras/Raf/MEK/ERK pathway occurs in more than 60% of BC indicating the importance of this pathway in biliary carcinogenesis. Furthermore anti-angiogenic agents such as the VEGF-antagonist bevacizumab, and the multikinase inhibitor sorafenib have been tested in BC in the first line setting with modest activity. Regorafenib is an oral multi-kinase inhibitor that targets multiple membrane-bound and intracellular kinases including VEGF, the Ras/Raf/MEK/ERK and PDGFR- ß pathways. Given the pivotal role of these pathways in biliary cancer biology, the clinical evaluation of regorafenib represents a novel and rational approach to treat this disease. Methods: This is a multi-institutional phase II single arm single-stage design trial using regorafenib as single agent. Patients with histologically or cytologically-proven locally advanced or metastatic biliary tract carcinomas that failed no more than 2 prior line of systemic chemotherapy are eligible for this study. Patients must have measurable disease per RECIST 1.1 criteria and never been treated with VEGF inhibitors. Patients will receive regorafenib 160 mg daily (21 days on and 7 days off) and will be evaluated for response every 2 cycles (1cycle = 28 days). The study’s primary endpoint is 6 month overall survival. Secondary endpoints are to define disease control, progression-free survival and toxicity related to treatment. Correlative biomarker studies using plasma samples will be performed to investigate levels of 40 relevant proteins associated with the above-mentioned pathways in the attempt to identify predictive markers of drug benefit. As per September 2015, twelve of the 39 planned patients have been accrued for the study. In addition to Moffitt Cancer Center, this trial will enroll patients at the UNC Lineberger Comprehensive Cancer Center and VCU Massey Cancer Center. Clinical trial information: NCT02115542