Background: Biliary tract cancers (BTCs) are rare and aggressive malignancies. The current standard of care for advanced BTC is gemcitabine (GEM) plus cisplatin . Although there is no established second-line treatment, regimens such as FOLFOX, XELOX, FOLFIRI, XELIRI, GEM, and capecitabine have activity. Nal-IRI contains IRI free base encapsulated in liposome nanoparticles which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral levels of SN-38 compared with IRI. FU/LV/nal-IRI has shown overall survival benefit and acceptable toxicity in patients (pts) with metastatic pancreatic adenocarcinoma following GEM-based therapy in the NAPOLI-1 trial. Methods: This is a single arm, open label, multicenter phase II study of pts with advanced BTC previously treated with gemcitabine plus platinum chemotherapy. Pts will receive nal-IRI 70 mg/m² IV over 90 minutes, LV 400 mg/m² IV over 30 minutes, and FU 2400 mg/m² over 46 hours, every 14 days. The primary objective is to determine progression-free survival (PFS) rate at 4 months (4mo) using RECIST v. 1.1 criteria and central radiology review. Response assessments will occur using imaging every 8 weeks. All pts who receive at least 1 dose of the study treatment will be eligible for the primary analysis. We will substitute pts who screen fail or do not begin treatment. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy is 3 months with a PFS_4mo of 30%. FU/LV/nal-IRI would be of interest if it could increase the PFS_4mo to 50% or higher. We will use a 2-stage Simon Minimax design. Using a one-sided α of 0.05 and 80% power, 39 pts will be required to detect a difference in PFS_4mo between 30% and 50%. Assuming a dropout rate of 10%, 44 pts will be enrolled across the 5 study sites. Enrollment began in Q2 2019. Clinical trial information: NCT04005339