Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy, developing most often in the setting of liver cirrhosis (Sohal et al Current Oncol Rep 2011; Gordan et al JCO 2020). For advanced disease, immunotherapy has now become standard of care – a combination of atezolizumab and bevacizumab has shown the best overall survival outcome so far (Finn et al NEJM 2020). For earlier stage disease, however, there is no systemic therapy standard. The best treatment for HCC in the setting of cirrhosis is a liver transplant allowing potential cure for both the cancer and cirrhosis. Nonetheless, 25-35% of patients fail to reach liver transplant because of disease progression while waiting for a transplant (Sinha et al, Hepatology 2019) and approximately 15% experience HCC recurrence after transplant (Mehta et al, Transplantation 2020). Taken together, this constitutes a large subset of this patient population who cannot achieve a cure. Given the success of immunotherapy in the advanced setting, it is imperative to study this in the pre-transplant setting, to improve the outcomes cited above. However, there is a theoretical risk of graft rejection with immunostimulatory treatment. Methods: This is a single-arm, open-label, Phase II, multicenter study designed to evaluate the safety and efficacy of durvalumab and tremelimumab for the treatment of HCC patients who have cirrhosis or portal hypertension and are eligible for listing for a liver transplant. Eligibility requirements include adult patients with HCC within UCSF criteria, a Child-Pugh score of up to 7, and ECOG PS of 0 or 1. Treatment includes an immunotherapy combination of 1 dose of tremelimumab and 5 doses of durvalumab for up to 4 months. After a minimum 28-day gap following the final durvalumab dose, patients undergo locoregional therapy per institutional standards. After a minimum 72-day gap from the end of immunotherapy, patients undergo liver transplant. Primary outcome is a binary endpoint, and it will be assessed in patients undergoing liver transplant. Historically, 10-20% of patients are expected to experience acute cellular rejection within 30 days of transplant. We propose that an observed proportion of 20% treatment failure will be a clear indicator of safety in this pilot study, whereas an observed proportion of 50% failure will be a clear indicator of failure. Using these guardrails, with at least 20 patients going to transplant, we will have 80.6% power to demonstrate a failure proportion of 20% (4 patients experiencing failure) versus a null of 50% (10 patients experiencing failure), with a one-sided alpha of 0.05. With 25 patients going to transplant, the power will increase to 86% (other parameters being the same). Clinical trial information: NCT05027425.