Inclusion

          -  Patients must have a pathologically confirmed carcinoma of the biliary tract
             (intra-hepatic, extra-hepatic (hilar, distal) or gall bladder) that is not eligible
             for curative resection, transplantation, or ablative therapies. Tumors with mixed
             hepatocellular and cholangiocarcinoma histology are excluded.

          -  Patients must have received one and only one prior systemic therapy for advanced
             disease. Prior therapies must have not included irinotecan or PD- 1/PD-L1 antibody.
             Patient should have either progressed on or within 6 months of first-line systemic
             therapy or deemed intolerant of that therapy.

          -  Prior surgical resection, radiation, chemoembolization, radioembolization or other
             local ablative therapies are permitted if completed ≥ 4 weeks prior to registration
             AND if patient has recovered to ≤ grade 1 toxicity.

          -  Patients must have radiographically measurable disease (as per RECISTv1.1) in at least
             one site not previously treated with radiation or liver directed therapy (including
             bland, chemo- or radio-embolization, or ablation) either within the liver or in a
             metastatic lesion.

          -  Age ≥18 years

          -  Child-Pugh score of less than 7

          -  ECOG performance status of 0-1

          -  Ability to understand and willingness to sign IRB-approved informed consent

          -  Available archived tissue (FFPE block or 20 unstained slides from prior core biopsy or
             surgery)

          -  Must be able to tolerate CT and/or MRI with contrast

          -  Adequate organ function (per protocol) assessed ≤2 weeks prior to registration

        Exclusion

          -  Must not have received systemic steroid therapy, or any other form of
             immunosuppressive therapy within 14 days prior to registration. Short bursts of
             steroids of 5-7 days (for COPD exacerbation or other similar indication) are allowed.

          -  No prior history of solid organ transplantation or brain metastasis (unless treated,
             asymptomatic and stable).

          -  Must not have undergone a major surgical procedure < 4 weeks prior to registration.

          -  Must not have an active second malignancy other than non-melanoma skin cancer or
             cervical carcinoma in situ. Patients with history of malignancy are eligible provided
             primary treatment of that cancer was completed > 1 year prior to registration and the
             patient is free of clinical or radiologic evidence of recurrent or progressive
             malignancy.

          -  Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours off
             antibiotics).

          -  Must not have received a live vaccine within 30 days of registration

          -  Must not have a psychiatric illness, other significant medical illness, or social
             situation which, in the investigator's opinion, would limit compliance or ability to
             comply with study requirements.

          -  Women must not be pregnant or breastfeeding since 5-fluorouracil, nal- irinotecan
             and/or nivolumab may harm the fetus or child. All females of childbearing potential
             (not surgically sterilized and between menarche and 1- year post menopause) must have
             a blood test to rule out pregnancy within 2 weeks prior to registration.

          -  Women of child-bearing potential and men must agree to use 2 methods of adequate
             contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study
             entry, for the duration of study participation, and for 5 months (for women) and 7
             months (for men) following completion of study therapy.

          -  Participants with an active, known or suspected autoimmune disease which may affect
             vital organ function, or has/may require systemic immunosuppressive therapy for
             management are excluded. Participants with type I diabetes mellitus, hypothyroidism
             only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or
             alopecia) not requiring systemic treatment, or conditions not expected to recur in the
             absence of an external trigger are permitted to enroll.

          -  Participants with a condition requiring systemic treatment with either corticosteroids
             (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of registration are excluded. Inhaled, ocular, intra-articular, intra-nasal or
             topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone
             equivalent, are permitted in the absence of active autoimmune disease.

          -  No known UGT1A1* variants or Gilbert's syndrome

          -  Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for
             treatment of either a psychiatric or physical (e.g. infectious disease) illness would
             be excluded.

          -  No known hypersensitivity to 5-fluorouracil, leucovorin, irinotecan, and/or nivolumab.

          -  Must not have ongoing bowel obstruction.

          -  No known HIV, Hepatitis B or Hepatitis C infection that is untreated and/or with a
             detectable viral load.

          -  Patients must not have uncontrolled intercurrent illness including, but not limited
             to, interstitial lung disease, symptomatic congestive heart failure, unstable angina
             pectoris, uncontrolled cardiac arrhythmia.

          -  No known medical condition (e.g. a condition associated with uncontrolled diarrhea
             such as ulcerative colitis or acute diverticulitis) that, in the investigator's
             opinion, would increase the risk associated with study participation or interfere with
             the interpretation of safety results.

          -  Patients must not be on warfarin, strong CYP3A4 inducers (such as phenytoin,
             phenobarbital, primidone, carbamazepine, rifampin, rifabutin, rifapentine or St.
             John's wort), strong CYP3A4 inhibitors (such as ketoconazole, clarithromycin,
             indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
             telaprevir, voriconazole), and strong UGT1A1 inhibitors (such as atazanavir,
             gemfibrozil, indinavir and ketoconazole).