Combined Treatment of Durvalumab, Bevacizumab, Tremelimumab and Transarterial Chemoembolization (TACE) in Subjects With Hepatocellular Carcinoma or Biliary Tract Carcinoma

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Most people with advanced HCC survive an average of 6 to 9 months. Researchers are evaluating a combination of treatment drugs to delay the progression of HCC; aiming to help people with HCC live longer. Objective: To study the 6-month progression-free survival in people with advanced HCC treated with bevacizumab, durvalumab, and TACE. Eligibility: Adults ages 18 and older with intermediate or advanced HCC Design: Participants will be screened with a physical exam and medical history. They will have tests to evaluate their hearts as well as blood and urine. A CT and/or MRI scans will be done during the study. If a prior tumor sample is not available; participants may undergo a biopsy. They may undergo an endoscopy of their esophagus and stomach. Participants will get the study drugs in 21-day cycles: Two treatment drugs will be injected into a vein every 3 weeks. Patients will have an interventional treatment procedure done by interventional radiology under sedation; chemotherapy beads will be infused into artery branches in the liver. Participants may have to stay in the hospital for 24 hours for observation, after this procedure. This interventional procedure may be done more than once during the study. Participants may need to repeat some of the screening tests throughout the study. Participants may have to stop taking some of their cancer treatment drugs during the study. Participants will continue on the study until their cancer progresses or until the side effects of the treatment drugs are not tolerable.

Background: * Worldwide, hepatocellular carcinoma (HCC) is the fourth most common cause of cancer related death with a median survival of 6-9 months. * Biliary tract carcinoma (BTC) is relatively uncommon and includes cancers of the gallbladder and intra- and extra-hepatic biliary ductal system, although periampullary tumors are often considered part of this group as well. * A class of agents that in the recent years has been at the epicenter of immunotherapy approaches in gastrointestinal malignancies are the monoclonal antibodies (mAbs) against the immune checkpoint inhibitors CTLA4, PD-1 and PD-L1. * Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1 ) subclass. Durvalumab inhibits binding of programmed cell death ligand 1 (PD-L1) to programmed cell death 1 (PD-1) and CD80. Anti-PD-L1 antibodies directly target tumor cells and are expected to have less adverse events in comparison with anti-PD-1 antibodies that target effector T-cells in the tumor microenvironment. * Tremelimumab is a human IgG2 mAb directed against CTLA-4. Tremelimumab blocks the inhibitory effect of CTLA-4, and therefore enhances T cell activation. * Angiogenesis is defined as the formation of new blood capillaries, which is a complex process that promotes vascular endothelial growth factor (VEGF) and other proangiogenic factor expression, thus enhancing metastasis. Inhibition of VEGF function by bevacizumab can lead to the inhibition of the new blood vessels formation surrounding a tumor, and consequently arrest the tumor growth by depriving essential nutrients and oxygen. * TACE has been shown to induce anti-tumor immunity. * Early phase studies have shown that anti-VEGF treatment with bevacizumab in combination with TACE decreases neovascular formation. * We have previously shown that locoregional therapies can be safely combined with immune checkpoint blockade. There are also preclinical data suggesting that anti-VEGF therapy may target myeloid cells with suppressor activity. Objectives: * To evaluate the 6-month progression free survival (PFS) in participants with advanced HCC BCLC stage B treated with bevacizumab, durvalumab, tremelimumab and TACE. * To evaluate the 6-month PFS in participants with BTC and HCC BCLC stage C treated with bevacizumab, durvalumab and tremelimumab. * In participants with BTC enrolled following amendment dated 03/2024, the primary objective will be: To determine if the PFS may be improved upon compared to data from a previous trial in the same participant population. Eligibility: * Histopathological confirmation of HCC or BTC or histopathological confirmation of carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of BTC. * Participants must have evaluable or measurable disease per RECIST 1.1. * Participants must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation. Design: * This is an open label Phase II trial conducted to evaluate efficacy of durvalumab, bevacizumab and tremelimumab combined treatment in participants with advanced HCC BCLC stage C or BTC and efficacy of durvalumab, bevacizumab, tremelimumab and TACE combined treatment in participants with advanced HCC BCLC stage B. * Initially 3-18 participants with HCC BCLC Stage C or BTC will be enrolled into safety run-in of Arm 1 to determine the safety of combined treatment of durvalumab, bevacizumab and tremelimumab. * Once safety has been determined, subsequent participants with HCC BCLC Stage C and BTC will be enrolled in Arm 1 and participants with HCC BCLC Stage B will start enrollment into Arm 2, consistent of durvalumab, bevacizumab, tremelimumab and multiple TACE procedures. * Once Arm 1 has completed accrual in the BTC cohort, Arm 3 will begin accruing participants with advanced unresectable or metastatic BTC, treated with durvalumab, bevacizumab, and tremelimumab using a different treatment schedule. * Treatment will continue until progression or unbearable toxicity.