Background: CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Presently, there is no consensus second-line therapy for patients with Biliary Tract Cancer (BTC) in whom first-line therapy has failed. In a Phase 1b study of CTX-009 in combination with paclitaxel, there were 4 patients with cholangiocarcinoma enrolled, and 2 of these 4 patients (both received CTX-009 at 10mg/kg + paclitaxel) had confirmed PRs with declines of 41.4% and 61.6% in their linear tumor burden from the baseline. Both of these patients had multiple prior therapies, and were on study for more than a year, with durable responses for more than 9 months each. Based on that observation, an adaptive Phase 2 cohort was added to the Phase 1b Study. There are currently 9 confirmed PRs among 24 patients treated for a 37.5% overall response rate in the ongoing Phase 2 Study of CTX-009 in combination with paclitaxel in patients with BTC treated in the second- or third-line setting. While there is anecdotal data suggesting that taxanes may have activity in BTC, the contribution of CTX-009 needs to be confirmed in a randomized study. Methods: CTX-009 is being evaluated in an open-label, randomized, controlled study in patients with previously treated, advanced or metastatic BTC. 120 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone. The stratification factors to be used at randomization include sex, presence of disease inside the liver only (intrahepatic cholangiocarcinoma) vs. outside the liver (all extrahepatic BTC or metastatic disease), and Eastern Cooperative Oncology Group (ECOG) Performance status (0 vs. 1). Patients will be treated in 28-day cycles, with CTX-009 administered at 10 mg/kg IV on Day 1 and 15, and paclitaxel administered at 80 mg/m2 on days 1, 8, and 15. The primary objective of the study is to assess the efficacy of CTX-009 in combination with paclitaxel vs. paclitaxel alone, as measured by Overall Response Rate (ORR) assessed by an Independent Central Radiology (ICR) review. Key secondary objectives include overall survival, progression-free survival, and duration of response. The study is currently activating sites with first patient in expected to be enrolled in 2022. Clinical trial information: NCT05506943.