A multicenter phase 1b/2 trial of gemcitabine, cisplatin, nab-paclitaxel, and tislelizumab (GENTIS) in treatment-naïve patients with locally advanced or metastatic biliary tract cancer.

TPS616 Background: Biliary tract cancers (BTCs) are aggressive malignancies with limited treatment options and poor prognosis. Since the ABC-02 trial established gemcitabine plus cisplatin (Gem/Cis) as the standard first-line regimen, overall survival has remained unsatisfactory. Recent phase 3 trials, such as TOPAZ-1 and KEYNOTE-966, demonstrated that the addition of immune checkpoint inhibitors (ICIs) to Gem/Cis improved survival, yet the incremental benefit was modest. Nab-paclitaxel has been shown to disrupt desmoplastic stroma and enhance drug delivery in pancreatic cancer and BTCs, although its efficacy in phase 3 trials was offset by toxicity. Tislelizumab, a novel PD-1 inhibitor, has demonstrated robust activity across multiple tumor types. We therefore designed the GENTIS trial (NCT06893380) to evaluate whether strategic low-dose nab-paclitaxel combined with Gem/Cis and tislelizumab could optimize efficacy while maintaining tolerability in treatment-naïve patients with advanced BTC. Methods: GENTIS (NCT06893380) is a prospective, multicenter, open-label, phase 1b/2 trial. In phase 1b, a 3+3 dose-escalation design determines the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of nab-paclitaxel combined with fixed-dose Gem/Cis and tislelizumab. In phase 2, a single-stage design with 49 patients is being conducted to assess efficacy at the RP2D. Eligible patients are ≥19 years with histologically confirmed, locally advanced, or metastatic BTC, ECOG performance status 0–1, and measurable disease by RECIST v1.1. Treatment consists of tislelizumab 200 mg on day 1 every 3 weeks, gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on days 1 and 8, and nab-paclitaxel at 50–100 mg/m² on days 1 and 8 of a 21-day cycle. The primary endpoints are MTD and RP2D in phase 1b, and objective response rate in phase 2. Secondary endpoints include progression-free survival, overall survival, disease control rate, duration of response, safety, and quality of life. Exploratory endpoints include biomarker analyses from tumor tissue and peripheral blood. Results: This trial is ongoing, with enrollment planned for 6–12 patients in phase 1b and 49 patients in phase 2 across seven Korean institutions. The first patient was enrolled in May 2025, and study completion is expected by April 2027. Conclusions: GENTIS (NCT06893380) is the first investigator-initiated trial to evaluate the combination of Gem/Cis, low-dose nab-paclitaxel, and tislelizumab in the first-line treatment of advanced BTC. This study is designed to determine whether stromal modulation and PD-1 inhibition added to chemotherapy can improve clinical outcomes while minimizing toxicity. The results will provide important evidence for developing novel chemo–immunotherapy platforms in BTC. Clinical trial information: NCT06893380 .