['cholangiocarcinoma']
['regorafenib/active', 'regorafenib/placebo']

        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
      