Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Cholangiocarcinoma

Inclusion Criteria: * Must have histologically-confirmed diagnosis of cholangiocarcinoma Stage II, III, or IV CCA (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are not allowed. * Must have radiographically measurable disease in at least one site not previously treated with radiation, chemoembolization, radioembolization, or other local ablative procedures; a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is acceptable. * May have received prior radiation, chemoembolization, radioembolization, or other local ablative therapies, or hepatic resection if completed ≥ 4 weeks prior to registration AND if patient has recovered to ≤ grade 1 toxicity. NOTE: Measurable disease (as required above) must still be present. * May have received prior radiation for bone or brain metastases if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) ≥ 2 weeks prior to registration. * Age ≥ 18 years. * Child-Pugh score of A or B with ≤ 7 points. * Eastern Cooperative Oncology Group performance status of 0-1. * Willing to provide archived tissue, if available, from a previous diagnostic biopsy. * Must be able to tolerate CT and/or MRI with contrast. * Adequate organ function obtained ≤ 2 weeks prior to registration: * Absolute Neutrophil Count ≥ 1500/mm³ * Hemoglobin ˃9.0 g/dL * Platelets ˃100,000/mm³ * Serum Creatinine ≤ 1.5x Upper Limit Normal (ULN) * Creatinine Clearance ≥ 50 mL/min * Albumin ≥ 2.8 g/dL * Total Bilirubin ≤ 1.5 mg/dL or ≤ 1.5x ULN * Aspartate Aminotransaminase (AST)/Alanine Aminotransaminase (ALT) ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases) * International Normalized Ratio (INR) \<1.5x the ULN \[INR ≥ 1.5 is allowed if anticoagulation is used.\] * Women must not be pregnant or breastfeeding since nab-paclitaxel and/or gemcitabine may harm the fetus or child. * Must not have received prior systemic cytotoxic chemotherapy or targeted therapy for this cancer. * Must not be receiving treatment with other investigational agents. * Must not have a pre-existing \>grade 2 peripheral neuropathy. * Must not be receiving immunosuppressive medications, including systemic corticosteroids, aside from the following exceptions: used for adrenal replacement, appetite stimulation, therapy for asthma, bronchitis exacerbation (≤ 2 weeks), anti-emesis, or pre-medication for procedures (i.e. CT scan). * No known Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) seropositivity. * Must not have undergone liver transplantation. * Must not have serious non-healing wound, ulcer, bone fracture, or abscess. * Must not have undergone a major surgical procedure \<4 weeks prior to registration. * Must not have possible histories of pneumonitis or pneumonitis risk factors. * Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ. * Must have no ongoing or active, uncontrolled infections. * Must have no evidence of significant, uncontrolled concomitant diseases including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, myocardial infarction within preceding 12 months, uncontrolled peripheral vascular disease, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, connective tissue disease including lupus. * Must not have any history of allergic reaction(s) attributed to compounds of similar composition to nab-paclitaxel or gemcitabine.