Cryoablation and Arterial Infusion of SD-101 in Combination With Durvalumab and Tremelimumab

The goal of this Phase 1b clinical trial is to evaluate the safety and efficacy of cryoablation and hepatic arterial administration of SD-101 in participants with advanced hepatocellular carcinoma. After this procedure, participants will be treated with tremelimumab and durvalumab every 4 weeks (STRIDE regimen).

Inclusion Criteria: * Willing and able to provide written informed consent prior to performance of any study- specific procedures. * Age ≥ 18 years. * Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic participants: 1. For cirrhotic participants with no histological confirmation of diagnosis, clinical confirmation is required per AASLD criteria. 2. Pathological diagnoses of HCC will be made according to the International Working Party criteria. * HCC with a component that measures at least 3 cm and that is located 1 cm or greater away from sensitive structures, including large blood vessels, large bile ducts, pericardium, diaphragm, gallbladder, stomach, and bowel. * Is not a candidate for local therapies alone, including liver transplantation, tumor ablation, transarterial embolization, radiation therapy, or resection. * No prior systemic therapy for advanced or metastatic HCC. * Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 * Evaluable target lesions as per Response Evaluation Criteria in Solid Tumors RECIST v1.1 or mRECIST. * Child-Pugh A or Child-Pugh B7 liver function. * Life expectancy of ≥ 12 weeks. * Adequate bone marrow function defined as: 1. Peripheral absolute neutrophil count ≥ 1000/mm\^3 2. Platelet count ≥ 50,000/ mm\^3 3. Hemoglobin ≥ 8.0 g/dL * Adequate renal function defined as creatinine clearance ≥ 50 ml/min * Adequate liver and pancreatic function defined as: 1. Total bilirubin ≤ 2.0 x institution's upper limit of normal, and 2. Alanine transaminase (ALT) or Aspartate transaminase (AST) ≤ 5 x institution's upper limit of normal, and 3. Albumin ≥ 2 g/dL * Adequate central nervous system function defined as: a. patients with seizure disorder may be enrolled if on anticonvulsants and seizures are well controlled. * Systolic blood pressure \