Background: Trebananib is a first-in-class antiangiogenic therapy that sequesters Ang1 and Ang 2, preventing their interaction with the Tie 2 receptor. A previous study of the combination of trebananib with sorafenib in renal cell carcinoma showed an acceptable toxicity profile. Elevated Ang 2 levels have been associated with a poor prognosis in HCC. We thus evaluated the safety and efficacy of trebananib plus sorafenib in HCC. Methods: Patients with HCC, ECOG ≤ 2, Childs-Pugh A, and adequate organ function received IV trebananib at 10mg/kg weekly (cohort 1) or 15 mg/kg weekly (cohort 2) plus sorafenib 400 mg PO twice daily. Thirty patients were accrued to each cohort to provide a power of 80% with the 1-sided exact test for single proportion at α = 0.20 to show a ≥ 78% PFS rate at 4 months relative to 62% reported in the sorafenib historical control. Secondary endpoints included safety and tolerability, progression free survival, objective response rate, disease control rate, time to progression, and overall survival. Results: See table. Conclusions: Trebananib at 10 mg/kg and 15 mg/kg plus sorafenib were well tolerated in patients with advanced HCC. When compared with historical controls, study results did not show an improvement in PFS rate at four months. Clinical trial information: NCT00872014.