A Pilot Study of Targeting Driver Oncogenes With a Peptide Vaccine Plus Durvalumab and Tremelimumab for Patients With Biliary Tract Cancers

Inclusion Criteria: * Age ≥18 years * Must have a histologically- or cytologically, proven biliary tract cancer (BTC) previously treated with gemcitabine/cisplatin/anti-PD(L)1 therapy. * Must have evidence of radiological disease, must accept to have a tumor biopsy of an accessible lesion at baseline and on treatment. * Must have sufficient archival tumor tissue for next-generation sequencing (NGS) and immune-phenotyping. * Have a BTC containing at least one of the oncogenic mutation/alterations targeted by the vaccine. * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. * Must have body weight of \>30 kg. * Patients must have adequate organ and marrow function defined by study-specified laboratory tests. * Patients with chronic or acute hepatitis B virus (HBV) or hepatitis C virus (HCV) infection must have disease controlled prior to enrollment. * Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test. * For both Women and Men, must use acceptable form of birth control while on study. * Must have a life expectancy of at least 12 weeks. * Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: * Participation in another clinical study with an investigational product during the last 2 weeks. * Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study. * Any of the following procedures or medications within 2 weeks prior to initiation of study treatment: * Systemic or topical steroids at immunosuppressive doses (\> 10 mg/day of prednisone or equivalent). The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) * Palliative or adjuvant radiation or gamma knife radiosurgery. * Chemotherapy or checkpoint inhibitor targeting anti-Pd1/PD-L1. * Within 4 weeks prior to initiation of study treatment: * Any investigational cytotoxic drug. * Any investigational device. * Non-oncology vaccines containing live virus. * Allergen hyposensitization therapy. * Growth factors, e.g. granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin. * Major surgery. * Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. * Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. * All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. * Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. * Patients with a history of prior treatment with anti-PD-1 and anti-PD-L1. * History of severe hypersensitivity reaction to any monoclonal antibodies or related compounds or to any of its components. * History of leptomeningeal carcinomatosis. * Patient has a known history or evidence of brain metastases. * Has an active known or suspected autoimmune disease or which has required systemic therapy in the last 5 years. * Known history of interstitial lung disease or of (non-infectious) pneumonitis that required steroids or current pneumonitis. * Has a pulse oximetry \< 92% on room air. * Requires the use of home oxygen. * Has a known history of Human Immunodeficiency Virus (HIV)/AIDS * Has active co-infection with HBV (hepatitis B virus) and HCV (hepatitis C virus) or coinfected with HBV and hepatitis delta virus (HDV) * Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements. * Patients who have been diagnosed with another cancer or myeloproliferative disorder in the past 5 years requiring systemic therapy or expected to require active therapy within the clinical study period. * Has a diagnosis of immunodeficiency. * Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded. * Any other sound medical, psychiatric, and/or social reason as determined by the Investigator. * Patient is at the time of signing informed consent a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol). * Patient is unwilling or unable to follow the study schedule for any reason. * Pregnant or breastfeeding. * WOCBP and men with female partners (WOCBP) who are not willing to use contraception. * Evidence of clinical ascites requiring paracentesis in the last 4 weeks. * History of malignant bowel obstruction.