Phase II study of neoadjuvant durvalumab and tremelimumab in combination with gemcitabine and cisplatin in patients with intrahepatic cholangiocarcinoma that is borderline resectable or resectable with high risk for recurrence.

TPS4198 Background: Finding effective and tolerable neoadjuvant treatment to downstage borderline resectable intrahepatic cholangiocarcinoma (ICC) could increase the rate of R0 resections and significantly improve patient outcomes. The combination of gemcitabine, cisplatin, and durvalumab based on the TOPAZ-1 trial is now the preferred first-line regimen for advanced, unresectable biliary tract cancer (1). The objective response rate (ORR) was 26.7% for the 3-drug regimen. Gemcitabine, cisplatin, durvalumab, and tremelimumab (an anti-CTLA4 antibody) in advanced, unresectable biliary tract cancer had an objective response rate of 70% in a phase II study (2). Given this response to immunotherapy plus chemotherapy, the 4-drug combination of gemcitabine, cisplatin, durvalumab, plus tremelimumab in the neoadjuvant setting may be able to improve the conversion rate of borderline resectable ICC to resectable ICC and improve R0 resection rates. Methods: This is an open-label, single-arm, multicenter phase II safety and feasibility study of neoadjuvant gemcitabine + cisplatin + durvalumab + tremelimumab in patients with ICC that is borderline resectable or resectable with a high risk of recurrence. 24 patients will receive 3-week cycles of durvalumab 1500 mg on D1, tremelimumab 300 mg only on C1D1, gemcitabine 1000mg/m 2 on D1 and D8, and cisplatin 25mg/m 2 on D1 and D8. Treatment will be stopped after C4 if a patient is able to proceed with surgery, otherwise they will complete 8 cycles and be re-evaluated for surgery at that point. Key eligibility criteria include no prior systemic therapy, histologically proved ICC, ECOG 0-1, and disease that is not readily suitable for resection with curative intent based on discussion with multidisciplinary committee including a hepatobiliary surgeon. Primary endpoints are feasibility and safety with secondary endpoints of overall survival, progression free survival, ORR, R0 resection rate, and pathologic complete response. Molecular biomarkers from blood to predict outcomes and organoid development from circulating tumor cells are exploratory endpoints. The study will be carried out in 2 stages. In stage 1, 11 patients will be accrued and the study will be stopped if 2 or fewer patients undergo resection based on a null hypothesis of a resection rate after neoadjuvant treatment of about 24%. Otherwise, 17 more patients will be accrued in stage 2 (assuming 15% dropout rate to hit target of 24) and if 9 or more of the 24 patients undergo resection, we will claim the treatment is feasible. The design has a type 1 error rate of 0.1 and power 0.8. Patient follow-up will be up to 3 years. The study is currently enrolling participants. 1. Oh et al. NEJM Evid 2022. 2. Oh et al. Lancet Gastroenterol Hepatol 2022. Clinical trial information: NCT06017297 .