Cabozantinib (XL-184) Monotherapy for Advanced Cholangiocarcinoma

Inclusion Criteria: * Participants must have unresectable or metastatic histologically or cytologically confirmed intrahepatic cholangiocarcinoma or extrahepatic cholangiocarcinoma (i.e. hilar and distal cholangiocarcinoma). * Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 20 mm with conventional techniques or as \> 10 mm with spiral CT scan. See section 10 for the evaluation of measureable disease. * Participants must have failed at least 1 but no more than 2 lines of systemic regimens for advanced cholangiocarcinoma due to disease progression or toxicity. * Age ≥ 18 years. * Life expectancy of ≥ 3 months. * ECOG performance status \< 1 (see Appendix A). * Participants must have adequate organ and marrow function as defined below: * Absolute neutrophil count \> 1,500/mcL * Platelets \> 100,000/mcL * Hemoglobin ≥ 9 g/dL * Total bilirubin ≤ 2.0 x the upper limit of normal * AST (SGOT)/ALT (SGPT) ≤ 5 X institutional upper limit of normal * PT/PTT ≤ 1.5 x ULN * Creatinine ≤ 1.5 or GFR ≥ 60 mL/min/1.73m2 * Lipase \< 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis * Serum phosphorus, calcium, magnesium and potassium ≥ LLN * Urine protein: creatinine ratio ≤ 1 * Serum Albumin ≥ 2.8 g/dl * Prior chemoembolization, radiofrequency ablation, or radiation to the liver is allowed as long as the patient has measurable disease outside of the treated area or measurable progression at the site of the treated area * Ability to understand and the willingness to sign a written informed consent document. * Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s). * Women of childbearing potential must have a negative pregnancy test at screening. Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as amenorrhea ≥ 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason. Exclusion Criteria: * Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study. * Prior treatment with cabozantinib or other VEGF-R directed therapies * Gallbladder carcinoma or periampullary tumors * Chemotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin) or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. * The subject has received radiation therapy: * to the thoracic cavity, abdomen or pelvis within 3 months of the first dose of study treatment or has with ongoing complications or is without complete recovery and healing from prior radiation therapy * to bone or brain metastasis within 14 days of the first dose of study treatment * to any other site(s) within 28 days of the first dose of study treatment * The subject has a primary brain tumor. * The subject has active brain metastases or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. (Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility.) * The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders including * Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening * Concurrent uncontrolled hypertension defined as sustained BP \> 140 mm Hg systolic, or \> 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment * Any history of congenital long QT syndrome * Any of the following within 6 months before the first dose of study treatment: * unstable angina pectoris * clinically-significant cardiac arrhythmias * stroke (including TIA, or other ischemic event) * myocardial infarction * thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study) * Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: * Any of the following within 28 days before the first dose of study treatment * intra-abdominal tumor/metastases invading GI mucosa * active peptic ulcer disease, * inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis * malabsorption syndrome * Any of the following within 6 months before the first dose of study treatment: * abdominal fistula * gastrointestinal perforation * bowel obstruction or gastric outlet obstruction * intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 6 months before the first dose of study treatment. * Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy * Other clinically significant disorders such as: * active infection requiring systemic treatment within 28 days before the first dose of study treatment * serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment * history of organ transplant * concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment * history of major surgery as follows: * Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications * Minor surgery within 1 months of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications * Clinically significant gastrointestinal bleeding within six months of the first dose of study treatment * Previous history of pulmonary embolism or deep venous thrombosis * Severely impaired lung function or history of interstitial lung disease * Concurrent malignancy (other than adequately treated non-melanoma skin cancer, superficial transitional cell carcinoma of the bladder, and cervical carcinoma in situ) diagnosed within the past 3 years or any currently active malignancy * Psychiatric illness/social situations that would limit compliance with study requirements. * The subject has a history of clinically significant hematemesis, hemoptysis of \> 2.5 mL of red blood, radiation (including brachytherapy) to pulmonary lesions, or signs indicative of significant pulmonary hemorrhage within 3 months before the first dose of study treatment. * The subject has radiographic evidence of cavitating pulmonary lesion(s) * The subject has a lesion abutting, invading, or encasing a major blood vessel. * The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib. * The subject has received any other type of investigational agent within 28 days before the first dose of study treatment. * The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) \>500 ms within 28 days before randomization. . Note: if initial QTcF is found to be \> 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard * History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib. * The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin, warafarin-related agents, heparin, thrombin inhibitors, Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic Low Molecular Weight Heparin (LMWH) are permitted. * The subject requires concomitant use of strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort) or strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir). * The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. Note: Subjects with prostate cancer currently receiving LHRH or GnRH agonists may be maintained on these agents. * The subject is unable to swallow tablets * Individuals who are known to be HIV-positive are excluded from this study. HIV positive individuals are at increased risk of lethal infection when treated with marrow-suppressive agents, and cabozantinib has not adequately been tested in this population. Also, antiretroviral therapy may have pharmacokinetic interactions with cabozantinib that have not been fully characterized yet. * Pregnant women are excluded from this study due to the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with cabozatinib, breastfeeding should be discontinued if the mother is treated with cabozantnib. These potential risks may also apply to other agents used in this study. * Subjects may not be receiving any other study agents concurrently while on this study