Background: Following surgical resection, the rate of recurrence of intrahepatic cholangiocarcinoma (ICC) is high. Expert groups recommend preoperative systemic therapy, particularly for resectable ICC with features that portend a high risk of recurrence. Based on data from ABC-02 the combination of gemcitabine and cisplatin (GC) is often used. This provides an objective response rate (ORR) of only 20% in ICC. The addition of durvalumab, an anti-PDL1 inhibitor to GC improves overall survival (OS) in the metastatic setting and is associated with an ORR of about 30%. On the other hand, while the addition of nab-Paclitaxel to GC provides an ORR of 34%, it was not associated with an improvement in OS in biliary tract cancer. It is therefore rationale to continue to explore and optimize immune checkpoint inhibitor development in ICC. We designed this study to determine the activity of durvalumab (D) and tremelimumab (T) (anti-CTLA4 ICPI) in combination with GC in resectable ICC with high-risk features. We plan to explore tumor intrinsic and tumor microenvironment related factors that will be associated with response (or lack thereof) to ICPI. Methods: This is a multicenter open-label, window of opportunity trial of the combination durvalumab and tremelimumab in combination with GC in resectable ICC with high-risk features. Inclusion criteria includes patients ≥18years with radiologically measurable and biopsy proven ICC that is surgically resectable but with high risk features (based on multidisciplinary tumor board discussion). Prespecified high-risk features include tumor size >5cm, T1b-T4 lesion, multifocal tumors/tumor with satellite lesions, suspicious or involved lymph nodes (N1) and vascular involvement all thought to be technically resectable. Patients with extrahepatic metastasis will be excluded. D will be administered at 1500mg IV on Day 1 every 3 weeks for up to a maximum of 4 cycles. T, 300mg will be administered on Day 1 of cycle 1 only. G (1000mg/m2) and C (25mg/m2) will be administered by IV infusion on Days 1 and 8 every 3 weeks for a maximum of 4 cycles. The primary outcome measure is to demonstrate an ORR of 52%. Secondary objectives are to assess the feasibility and safety of the combination in ICC. Given the historical objective response rate of 25% and using one-sided exact test for single proportion, we will have 80% power to reject 25% ORR at α=0.05 when we observe ORR of 52% (Ho: Po=0.25 vs. Ha: Pa=0.52) from the study sample. The study is open at the O’Neal Comprehensive Cancer Center at the University of Alabama and will be open at other centers in the next few months. Clinical trial information: NCT04989218.