TheraSphere With Durvalumab and Tremelimumab for HCC

Inclusion Criteria: 1. Participants must be aged ≥18 years at the time of screening. 2. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and accountability Act in the US, European Union (EU) data privacy regulations in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 3. Life expectancy ≥6 months. 4. HCC, diagnosed by radiographic imaging or histology. 5. Patient not a candidate for liver resection, thermal ablation, or transplantation at the time of study entry. 6. ECOG 0 or 1 7. Measurable disease by mRECIST criteria (e.g. ≥10mm of enhancement). 8. Tumor volume ≤35% of whole liver volume (determined by imaging). 9. Future liver remnant volume (FLRV) ≥30% of whole liver volume. FRLV is the volume of liver not planned to be treated with TheraSphere and free of HCC. 10. Dosimetry criteria for tumor(s) and normal tissue can be determined. 11. Patients with previous liver resection or ablation ≥6 months from end of previous treatment to TheraSphere administration. 12. Previous transarterial chemoembolization (TACE) is permitted if: 1. Previous TACE performed ≥8 months before TheraSphere administration and 2. Result of previous TACE was CR and 3. Current tumor is not a recurrence of previously treated lesion 13. Patients with portal vein thrombosis (PVT) Vp0, Vp1, or Vp2. 14. Patients with HBV or HCV infection are to have documented virology status of hepatitis as confirmed by HBV and HCV serology test: 1. Patients with HBV infection: HBV DNA load should be ≤2000 IU/mL obtained within 42 days prior to initiation of study treatment, and Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study 2. Patients with chronic HCV infection are allowed in the study: for untreated patients, AST/ALT should be ≤3xULN and for treated patients, antiviral treatment (per local standard of care) should be stopped for a minimum of 14 days prior to study entry and AST/ALT should be ≤3xULN 15. Patients with Human Immunodeficiency Virus (HIV) infection are eligible, provided the HIV infection is well controlled with no current or previous AIDS-related complications and CD4+ T-cell (CD4+) counts ≥ 350 cells/uL 16. Negative serum pregnancy test in females of childbearing potential. 17. Adequate contraception for the patient and his/her sexual partner. 18. Adequate renal and marrow function as defined below: 1. Hemoglobin (hgB) ≥9.0 g/dL 2. Absolute neutrophil count (ANC) ≥1.5 x 109/L 3. Platelet count ≥75 x 109/L 4. Measured or calculated creatinine clearance ≥45 mL/min as determined by Cockcroft-Gault (using actual body weight) 19. Absolute lymphocyte count ≥0.5 X 109/L 20. Adequate liver function, as defined by 1. Child-Pugh A 2. Albumin-bilirubin (ALBI) score 1 or 2 with upper limit for ALBI score ≤ -2. Patients with confirmed Gilbert's syndrome may not have an evaluable bilirubin value; therefore, ALBI score should not be considered for such patients. Patients with Gilbert's syndrome will be eligible with any bilirubin value, as long as Albumin level is ≥ 34 g/L. 3. AST and ALT \<3 x ULN. 21. Body weight \>30 kg and BMI ≥18 kg/m2. Exclusion Criteria: 1. Any contraindication to angiography or selective visceral catheterization. 2. Cone Beam CT (CBCT) or Technetium-99m macroaggregated Albumin (99mTc-MAA) hepatic arterial perfusion scintigraphy shows any deposition to the gastrointestinal tract that may not be corrected by angiographic techniques. 3. 99mTc-MAA hepatic arterial perfusion scintigraphy shows poor tumor and/or portal vein thrombosis (PVT) targeting that would lead to a dose that does not meet the liver dosing criteria. 4. Shunting of blood to the lungs that could result in delivery of \>30 Gy to the lungs in a single treatment or \>50 Gy cumulative dose to the lungs in case of multiple TheraSphere treatments, as seen on 99mTc-MAA hepatic arterial perfusion scintigraphy. 5. Vp3, Vp4, hepatic vein invasion, or inferior vena cava (IVC) invasion 6. Extrahepatic metastases (patients with extrahepatic spread \[EHS\]): 1. EHS is any extrahepatic lesion that, according to clinical symptoms, histology, or imaging data, is highly suspicious of being metastases. 2. For patients with bone pain/neurological symptoms (deficit, seizure or else) at baseline and suspected of metastases at screening, a bone scan/brain MRI is recommended prior to study entry. 3. Extrahepatic non-target non-measurable lesions (\<1 cm per RECIST 1.1) are acceptable if considered not suspicious by the investigator. 7. Any previous systemic HCC treatment 8. Prior exposure to immune mediated therapy for other disease, such as other anti-PD- 1, anti-PDL-1, anti-PDL-2, anti-CTLA-4, antibodies, etc. 9. Previous liver radiation (external beam radiation therapy (EBRT) or peptide receptor radionuclide therapy (PRRT)). 10. Concurrent treatment for HCC or treatment in the last 4 weeks in another clinical study, unless it is an observational study (non-interventional) or during a non-interventional follow-up stage of an interventional study, or prior inclusion in this study 11. Hepatic encephalopathy present at study entry and/or episodes of encephalopathy (Grade ≥ 2) within 6 months prior to study inclusion. 12. HCC with infiltrative disease that is not evaluable by mRECIST. 13. Pulmonary insufficiency (defined by an arterial oxygen pressure (PaO2) of \<60 mmHg, or oxygen saturation (SaO2) of \<90% (Roussos \& Koutsoukou, 2003) or clinically evident chronic obstructive pulmonary disease (COPD)). 14. Medical history of radiation pneumonitis or recent pneumonitis, regardless of causality 15. History of any organ allograft, including bone marrow allo and autograft. 16. History of active primary/acquired immunodeficiency, that makes patients unsuitable for additional immunotherapy in this study (per investigator and as detailed in exclusion criterion #18). 17. Active or prior documented autoimmune or inflammatory disorders (including but not limited to, inflammatory bowel disease \[e.g. ulcerative colitis or Crohn's disease\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion: 1. Patients with vitiligo or alopecia 2. Patients with hypothyroidism (e.g. following Hashimoto's syndrome) stable on hormone replacement therapy 3. Any chronic skin condition that does not require systemic therapy. 4. Patients without active disease in the last 5 years may be included but only after consultation with the Sponsor Study physician. 5. Patients with celiac disease controlled by diet alone. 18. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: 1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra-articular injection) 2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. 3. Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication). 19. History of gastrointestinal bleeding within 42 days prior to study inclusion, active GI bleeding and any bleeding diathesis or coagulopathy that is not correctable by usual therapy or hemostatic agents (e.g. closure device). Patients with known varices that have not bled or which have been clinically addressed can enter the study. No endoscopic exploration is required before study inclusion. 20. Presence of biliary stent or sphincterotomy within one year prior to study inclusion. 21. History of malignancy, other than HCC, within three years, except the condition is one of the following: 1. Adequately treated carcinoma in situ of the cervix, early squamous cell carcinoma or basal cell carcinoma of the skin, localized prostate cancer, breast ductal carcinoma in situ, or low-grade endometrial carcinoma with no myometrial invasion 2. Localized prostate cancer under active surveillance. 3. Other cancer when there is a negligible risk of recurrence or progression or death (5-year OS rate \> 90%). 22. Major surgical procedure (as defined by the Investigator) within 42 days prior to study inclusion. 23. A history of severe allergy or intolerance to contrast agents, narcotics, sedatives or atropine that cannot be managed medically. 24. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients that cannot be managed medically. 25. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), HBV and HVC co-infection, HBV and Hep D co-infection, human immunodeficiency virus (HIV 1/2 antibodies) plus HCV or HBV co-infection. 26. Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab and/or tremelimumab. Note: patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and/or tremelimumab and up to 30 days after the last dose of durvalumab and/or tremelimumab. 27. Female patients who are pregnant or breastfeeding and who do not want to stop breastfeeding. Male or female patients of reproductive potential who are not willing to employ any effective birth control method from screening and for at least 90 days after TheraSphere administration, 90 days after the last dose of durvalumab, and 6 months after the last dose of tremelimumab. 28. Unstable chronic disease or evidence of any disease or condition that would place the patient at undue risk and preclude safe use of TheraSphere, durvalumab and tremelimumab treatment as deemed by the site principal investigator. 29. Patients who are not able to follow the TheraSphere, durvalumab or tremelimumab treatment requirements. For France Patients Only 30. Persons deprived of their liberty by a judicial or administrative decision, persons subject to psychiatric care under articles L. 3212-1 and L. 3213-1 who are not covered by the provisions of Article L. 1121-8 and persons admitted to a health or social establishment for purposes other than research, including: 1. Pregnant, parturient, breast-feeding women (see also inclusion criterion 16 and exclusion criterion 27) 2. Minors (see also inclusion criterion 1) 3. Persons receiving psychiatric treatment (see also exclusion criteria 28) 4. Persons admitted to a health or social establishment for purposes other than research 5. Person of full age under curatorship 6. Adult subject to a mandate for future protection, a family authorization, or a guardianship measure 7. Person not affiliated or not beneficiary of a social security scheme