Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis with a median overall survival (OS) less than 12 months. This randomized, multi-institutional, phase 2, two-arm study is designed to investigate the role of combinational immunotherapy, using nivolumab with chemotherapy (gemcitabine/cisplatin) or as dual immunotherapy (nivolumab and ipilimumab) in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary adenocarcinoma (intrahepatic or extrahepatic and gallbladder) without prior systemic treatment, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease and/or chronic steroid use. Primary objective is to evaluate the progression-free survival (PFS) rate at 6 months. Secondary objectives include evaluation of overall response rate (ORR), median PFS and OS and safety in this patient population. Exploratory objectives include identification of biomarker predictors of response and mechanisms of resistance through serial (before, on and post therapy) biopsies and blood collection, including sequential whole exome/transcriptomic analysis and immune cell subset analysis (tissue and blood). Arm A therapy provides gemcitabine 1000 mg/m², cisplatin 25 mg/m² on days 1, 8 with nivolumab 360 mg on day 1 every 3 weeks for 6 months. In the absence of disease progression, pts may continue single agent nivolumab for up to 2 years. Arm B therapy includes nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks for up to 2 years in absence of disease progression. Accrual goal is 32 evaluable pts per arm. Using a null hypothesis value of 59% median PFS at 6 months, and an 80% alternative hypothesis, this ongoing study has > 80% power, with a one-sided alpha of 0.05 to identify treatment efficacy in one or both study arms. Clinical trial information: NCT03101566