The investigators are doing this study to learn if a combination of immunotherapy and a liver-directed tumor procedure can safely and effectively shrink or control liver cancer (hepatocellular carcinoma, HCC). The goal is to try to lower the stage of the cancer so that more patients may become eligible for a liver transplant. The investigators will also closely watch for side effects from the study treatments. Section 2 has more details.

The investigators are doing this study to learn if a combination of immunotherapy and a liver-directed tumor procedure can safely and effectively shrink or control liver cancer (hepatocellular carcinoma, HCC). The goal is to try to lower the stage of the cancer so that more patients may become eligible for a liver transplant. The investigators will also closely watch for side effects from the study treatments.

What are the study treatments? The patients will receive immunotherapy medicines through a vein (IV). The first treatment is a combination of tremelimumab and durvalumab, called STRIDE. After that, the patients may continue durvalumab about once every 4 weeks up to total of 12 cycles on study. The patients will also have a liver-directed tumor treatment (LRT), which is a procedure to treat the tumor inside the liver. Depending on what is best for the patients, this may include Yttrium-90 (Y90) (radiation delivered inside the liver), TACE (chemotherapy delivered directly to the liver tumor through a small tube placed in a blood vessel), or RFA (heat used to destroy the tumor). These procedures are done by a specialist using imaging guidance, and the patients may receive medicine to help the patients relax or sleep. The patients will be monitored during and after the procedure.

The patients are being asked to take part in this research study because the patients have intermediate or advanced hepatocellular carcinoma (HCC).

The U.S. Food and Drug Administration (FDA) has approved those drugs as they are being used in this study.

Another purpose of this study is for researchers to learn if a biomarker test is helpful in determining long-term effects of ICI. A biomarker is a biological molecule found in blood, other body fluids or tissues. Biomarkers may be a sign of a condition or disease. Biomarkers also can be used to predict patient's response to a specific treatment.

The study will include up to 41 patients total.

Inclusion Criteria:

1. Age ≥ 18 at the time of signing the Informed Consent Form.

2. Beyond UCSF criteria HCC with diagnosis confirmed histologically/cytologically, radiologically, or clinically per AASLD criteria, with life expectancy of at least 12 months.

3. Histologically confirmed HCC via liver biopsy obtained within 3 months prior to initiation of study treatment as part of SOC. If no historical biopsy is available, a biopsy must be performed at screening for confirmation. Screening liver biopsy may be conducted as part of research activities if not performed per SOC practice.

4. ECOG performance status ≤ 2 within 7 days prior to initiation of study treatment.

   Child-Pugh A or B7 (5 to 7 points) at screening and within 7 days prior to study treatment. D1 ECOG/CTP may not repeat if screening ECOG/CTP collected within 7 days prior to D1.

5. HCC with Measurable disease by mRECIST (see Appendix 11.2) (at least one ≥10mm target lesion) that is not suitable for resection per standard clinical practice and beyond UCSF criteria (see section 11.5) confirmed with most recent imaging obtained within 3 months prior to screening.

6. For subjects of childbearing potential (SOCBP), negative serum or urine pregnancy test and agreement to use adequate contraception or abstinence from the time of screening until 3 months following the last dose of Durvalumab.

7. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study.

Exclusion Criteria:

• 1- Known fibrolamellar HCC, sarcomatoid HCC, other rare HCC variant, or mixed cholangiocarcinoma and HCC.

  2- Extrahepatic spread with organ involvement other than liver. 3- Portal vein tumor thrombus (VP3-4) or any viable hepatic vein tumor thrombus at screening.

  4- History of immune therapy exposure (and-PD-1, and PDL-1, and anti-CTLA-4) treatment.

  5- Is pregnant or breastfeeding or expecting to conceive or impregnate someone during the study period.

  6- Active or history of autoimmune diseases, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis.

  7- Patient lacks interest or inadequate psychosocial support for organ transplantation.

  8- Patients who have a known concurrent malignancy that is progressing or requires active treatment, who have not completely recovered from prior treatment, or who have a significant malignancy history that, in the opinion of the investigator, should preclude participation.

  9- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.

  10- Active tuberculosis (TB), as documented by a positive purified protein derivative (PPD) skin test or TB blood test and confirmed by a positive chest X-ray within 3 months prior to initiation of study treatment.

  11- Active co-infection with HBV and HCV. Participants with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV.

  12- Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion of the investigator, could impact participant safety.

  13- Treatment with investigational therapy within 28 days prior to initiation of study treatment.

  14- Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.

  15- Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

  • Participants who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible.

  • Participants who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

    16- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment, within 5 months after the final dose of ICI.

    17- Radiotherapy within 28 days, or abdominal/pelvic radiotherapy within 60 days, prior to initiation of study treatment.

    18- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment; or abdominal surgery, abdominal interventions, or significant abdominal traumatic injury within 60 days prior to initiation of study treatment; anticipation of need for major surgical procedure during the course of the study; or non-recovery from side effects of any such procedure.

    19- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of the study drugs, may affect the interpretation of the results, or may render the participant at high risk from treatment complications