Background: There is currently an unmet medical need for patients with advanced biliary cancer (BC) who have failed one prior gemcitabine based systemic therapy.Regorafenib is an oral multi-kinase inhibitor that targets both receptor tyrosine kinases (RTKs), as well as the tumor cell proliferation/survival signaling pathway kinases (RAS/RAF/MEK/ERK). Methods: Pts with histologically proven BC who progressed on at least one line of systemic therapy received regorafenib 160 mg daily 21 days on 7 days off in a 28 days cycle. The single arm design was used to access 6 month overall survival (OS) as a primary endpoint. The study tested the null hypothesis of ≤30% of OS at 6 month against the alternative of ≥50% of OS at 6 month (HR = 0.578 ). With one-sided α of 10% and 86% power, the experimental treatment was deemed to have good activity if ≥14 out of 32 evaluable patients (43.8%) survive 6 months or longer. The secondary objectives included median OS, RR and PFS. Results: Thirty nine pts received at least 1 dose of regorafenib of whom 32 pts were evaluable for efficacy. Twenty pts failed 1 line of therapy and 12 pts failed two lines of therapy. Median age was 62 (range: 27-88) years and the primary sites of tumor were intrahepatic cholangiocarcinoma (68.8%), extrahepatic (18.8%), and gallbladder (12.5%). Pts were considered evaluable for efficacy if patients received more than 1 cycle of regorafenib. Seven pts were not evaluable because one pt withdrew consent, 5 pts expired due to clinical progression within a month and 1 pt due to toxicity. For 32 evaluable pts, 6 month OS was 50.9% (95% CI: 32.1%-67.0%), 12 month OS was 35% (95% CI 16.2-53.7) and 18 month OS was 35% (95% CI 16.2-53.7). Median PFS was 3.7 months (95% CI: 2.3-5.5) and median OS was 9.9 months (95% CI: 3.7-20.1). PR was achieved in 2 (6.2%) pts, SD in 18 (56.2%) pts with DCR of 62.4%. The overall toxicity profile was as expected with grade 3/4 AE of 71.8%. The most common adverse events were fatigue (56.4%) and hypertension (53.8%). Dose modification was required in 49% of the patients. Plasma samples were collected in all pts with planned correlative studies underway. Conclusions: The primary endpoint was met in this study. Further randomized trials are warranted to confirm the efficacy Clinical trial information: NCT02115542