Study protocol: a phase II study of trifluridine/tipiracil plus liposomal irinotecan as second-line therapy in advanced biliary tract cancer (TRITICC 2)

Abstract Background The prognosis of patients with advanced biliary tract cancer progressing after gemcitabine-based first-line therapy remains poor. Effective second-line treatment options are limited, and outcomes with currently available regimens are modest. Trifluridine/tipiracil (FTD/TPI) and nanoliposomal irinotecan (nal-IRI) have demonstrated clinical activity in gastrointestinal malignancies and may provide synergistic antitumor effects. Methods TRITICC-2 is an investigator-initiated, prospective, open-label, multicenter, single-arm phase II trial conducted at academic centers in Germany. The study evaluates the efficacy and safety of FTD/TPI in combination with nal-IRI in patients with histologically confirmed, unresectable or metastatic biliary tract cancer who have progressed on gemcitabine-based first-line therapy. A total of 38 patients are planned for enrollment. Treatment consists of oral FTD/TPI administered on days 1–5 combined with intravenous nal-IRI on day 1 of a 14-day cycle, continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), safety, and health-related quality of life. An optional translational research program includes serial liquid biopsies and biomarker analyses. Enrollment is ongoing, with recruitment initiated in late 2025. Efficacy, safety, and translational analyses are pending. Conclusion TRITICC-2 investigates a biologically rational combination of FTD/TPI and nal-IRI in a patient population with a high unmet medical need. The study is expected to provide prospective data on the clinical activity and safety of this regimen and may contribute to the identification of biomarkers associated with treatment response in advanced biliary tract cancer. Trial registration EUCT 2024-517330-18-00.