Regorafenib Versus Placebo to Treat Cholangiocarcinoma

Inclusion Criteria: * histologically proven intra-hepatic or hilum cholangiocarcinoma (mass forming, not "liniting" tumor), locally advanced unresectable or metastatic * progression documented after GEM-CDDP (or GEM-OX), or gemcitabine alone followed or preceded by platinum-based (CDDP or oxaliplatin) chemotherapy * age \> 18 years * ECOG PS 0/1 at study entry * measurable disease according to RECIST version 1.1 * Adequate bone marrow, liver and renal function as assessed by the following laboratory requirementsconducted within 7 days of starting to study treatment: oSerum creatinine \<1.5x upper reference range oTotal bilirubin \<1.5x ULN oAlanine transaminase (ALT) and aspartate aminotransferase (AST) \< 2.5x ULN (\<5x ULN forpatients with liver involvement of their cancer). oAmylase and lipase \<1.5x ULN. * life expectancy of at least 12 weeks * effective contraception for both male and female patients if the risk of conception exists * negative proteinuria on dipstick or 24 hours proteinuria\<1000mg * signed written informed consent Exclusion Criteria: * unability to take oral medication * any malabsorption condition * patients taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg. Clarithromycin, indinavir,itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin,voriconazole) or strong CYP3A4 inducers (eg. Carbamazepine, phenobarbital, phenytoin, rifampin, St-John's Wort) (see section 8) * persistent proteinuria \>3.5g/24 hours measured by urine protein-creatinine ratio from a random urinesample (persistent proteinuria \>3 non-healing woud, ulcer, or bone fracture * any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of studymedication * interstitial lund disease with ongoing signs and symptoms at the time of informed consent * uncontrolled concurrent CNS, cardiac, infectious diseases, hypertension * history of myocardial infarction, deep venous or arterial thrombosis, cerebrovascular accident (CVA) during the last 6 months * previous exposure to anti-VEGF targeting therapy (including Regorafenib) and to signal transduction inhibitors * known hypersensitivity to any of the components of study treatments * previous malignancy in the last past 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix * pregnant or lactating women, or patients of both genders with procreative potential not using adequate contraceptive methods * medical or psychological conditions that would not permit the patient to complete the study or sign inform consent * unstable angina, congestive heart failure ≥NYHA class II * uncontrolled hypertension despite optimal management (systolic blood pressure \>150 mmHg or diastolic pressure \> 90mmHg) * pheochromocytoma * HIV infection * active chronic hepatitis B or C with a need for antiviral treatment * liver failure, cirrhosis Chil Pugh B or C * brain metastasis * major surgery, open biopsy or significant traumatic injury within 4 weeks prior to the first dose of treatment * intra-hepatic locoregional therapy (DC Beads, SIRT) * history of organ allograft * ongoing infection * renal failure requiring dialysis * patients receiving or having received any investigational treatment within 4 weeks prior to study entry, or participating to another clinical study