Background: Biliary tract cancers (BTC) currently account for ̃15% of all primary liver cancers and ̃3% of gastrointestinal malignancies. Gemcitabine/Cisplatin has been the standard of care in the first-line therapy of BTC for a decade. Despite recently some survival benefit has been shown in adding a checkpoint inhibitor, further lines of treatment are only poorly defined. In the ABC-06 phase-3 study, second-line FOLFOX demonstrated a moderate but significant improvement of survival and might be regarded as a standard of care. The combination of liposomal Irinotecan and 5-FU infusion pump also improved survival after first line therapy. Both mentioned second-line regimens are based on limited evidence and questionable generalizability. Thus, there is a high need for novel treatment concepts in patients without targetable genetic alterations. Trifluridine/tipiracil (FTD/TPI) is a orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Recent reports provided evidence of an antitumor activity of FTD/TPI plus Irinotecan as well in patients with BTC. Therefore, the TRITICC trial was designed to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with BTC refractory to previous Gemcitabine based treatment. Methods: TRITICC (NCT04059562) is an interventional, prospective, open-label, non-randomized, exploratory, multicenter, single-arm phase IIA clinical trial that evaluates the safety and efficacy of FTD/TPI (25 mg/m² body surface area (BSA), BID, orally on days 1-5 followed by a 9-days recovery period from day 6 trough day 14 of each 14-days treatment cycle) plus irinotecan (on day 1 of each cycle at a dose of 180 mg/m²) in adult patients with histologically verified locally advanced or metastatic BTC (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy. A total of 28 patients is planned to be enrolled in 6 sites across Germany. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment. Currently, 3 out of the planned 6 German study sites are opened for recruitment and 6 patients have been enrolled. The primary study endpoint is estimated to be evaluated in 2023. Clinical trial information: NCT04059562.