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., HealthInsurance Portability and accountability Act in the US, European Union (EU) dataprivacy regulations in the EU) obtained from the patient/legal representative priorto 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 atthe 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 ofliver 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 previoustreatment to TheraSphere administration.

12. Previous transarterial chemoembolization (TACE) is permitted if:

13. Previous TACE performed ≥8 months before TheraSphere administration and

14. Result of previous TACE was CR and

15. Current tumor is not a recurrence of previously treated lesion

16. Patients with portal vein thrombosis (PVT) Vp0, Vp1, or Vp2.

17. Patients with HBV or HCV infection are to have documented virology status ofhepatitis as confirmed by HBV and HCV serology test:

18. 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 (perlocal standard of care; e.g., entecavir) for a minimum of 14 days prior tostudy entry and willingness to continue treatment for the length of the study

19. Patients with chronic HCV infection are allowed in the study: for untreatedpatients, AST/ALT should be ≤3xULN and for treated patients, antiviraltreatment (per local standard of care) should be stopped for a minimum of 14days prior to study entry and AST/ALT should be ≤3xULN

20. Patients with Human Immunodeficiency Virus (HIV) infection are eligible, providedthe HIV infection is well controlled with no current or previous AIDS-relatedcomplications and CD4+ T-cell (CD4+) counts ≥ 350 cells/uL

21. Negative serum pregnancy test in females of childbearing potential.

22. Adequate contraception for the patient and his/her sexual partner.

23. Adequate renal and marrow function as defined below:

24. Hemoglobin (hgB) ≥9.0 g/dL

25. Absolute neutrophil count (ANC) ≥1.5 x 109/L

26. Platelet count ≥75 x 109/L

27. Measured or calculated creatinine clearance ≥45 mL/min as determined byCockcroft-Gault (using actual body weight)

28. Absolute lymphocyte count ≥0.5 X 109/L

29. Adequate liver function, as defined by

30. Child-Pugh A

31. 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 bilirubinvalue; therefore, ALBI score should not be considered for such patients.Patients with Gilbert's syndrome will be eligible with any bilirubin value, aslong as Albumin level is ≥ 34 g/L.

32. AST and ALT <3 x ULN.

33. 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) hepaticarterial perfusion scintigraphy shows any deposition to the gastrointestinal tractthat may not be corrected by angiographic techniques.

3. 99mTc-MAA hepatic arterial perfusion scintigraphy shows poor tumor and/or portalvein thrombosis (PVT) targeting that would lead to a dose that does not meet theliver dosing criteria.

4. Shunting of blood to the lungs that could result in delivery of >30 Gy to the lungsin a single treatment or >50 Gy cumulative dose to the lungs in case of multipleTheraSphere treatments, as seen on 99mTc-MAA hepatic arterial perfusionscintigraphy.

5. Vp3, Vp4, hepatic vein invasion, or inferior vena cava (IVC) invasion

6. Extrahepatic metastases (patients with extrahepatic spread [EHS]):

7. EHS is any extrahepatic lesion that, according to clinical symptoms, histology,or imaging data, is highly suspicious of being metastases.

8. For patients with bone pain/neurological symptoms (deficit, seizure or else) atbaseline and suspected of metastases at screening, a bone scan/brain MRI isrecommended prior to study entry.

9. Extrahepatic non-target non-measurable lesions (<1 cm per RECIST 1.1) areacceptable if considered not suspicious by the investigator.

10. Any previous systemic HCC treatment

11. 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.

12. Previous liver radiation (external beam radiation therapy (EBRT) or peptide receptorradionuclide therapy (PRRT)).

13. Concurrent treatment for HCC or treatment in the last 4 weeks in another clinicalstudy, unless it is an observational study (non-interventional) or during anon-interventional follow-up stage of an interventional study, or prior inclusion inthis study

14. Hepatic encephalopathy present at study entry and/or episodes of encephalopathy (Grade ≥ 2) within 6 months prior to study inclusion.

15. HCC with infiltrative disease that is not evaluable by mRECIST.

16. Pulmonary insufficiency (defined by an arterial oxygen pressure (PaO2) of <60 mmHg,or oxygen saturation (SaO2) of <90% (Roussos & Koutsoukou, 2003) or clinicallyevident chronic obstructive pulmonary disease (COPD)).

17. Medical history of radiation pneumonitis or recent pneumonitis, regardless ofcausality

18. History of any organ allograft, including bone marrow allo and autograft.

19. History of active primary/acquired immunodeficiency, that makes patients unsuitablefor additional immunotherapy in this study (per investigator and as detailed inexclusion criterion #18).

20. Active or prior documented autoimmune or inflammatory disorders (including but notlimited 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:

21. Patients with vitiligo or alopecia

22. Patients with hypothyroidism (e.g. following Hashimoto's syndrome) stable onhormone replacement therapy

23. Any chronic skin condition that does not require systemic therapy.

24. Patients without active disease in the last 5 years may be included but onlyafter consultation with the Sponsor Study physician.

25. Patients with celiac disease controlled by diet alone.

26. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab. The following are exceptions to this criterion:

27. Intranasal, inhaled, topical steroids, or local steroid injections (e.g.intra-articular injection)

28. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent.

29. Steroids as premedication for hypersensitivity reactions (e.g. CT scanpremedication).

30. History of gastrointestinal bleeding within 42 days prior to study inclusion, activeGI bleeding and any bleeding diathesis or coagulopathy that is not correctable byusual therapy or hemostatic agents (e.g. closure device). Patients with knownvarices that have not bled or which have been clinically addressed can enter thestudy. No endoscopic exploration is required before study inclusion.

31. Presence of biliary stent or sphincterotomy within one year prior to studyinclusion.

32. History of malignancy, other than HCC, within three years, except the condition isone of the following:

33. Adequately treated carcinoma in situ of the cervix, early squamous cellcarcinoma or basal cell carcinoma of the skin, localized prostate cancer,breast ductal carcinoma in situ, or low-grade endometrial carcinoma with nomyometrial invasion

34. Localized prostate cancer under active surveillance.

35. Other cancer when there is a negligible risk of recurrence or progression ordeath (5-year OS rate > 90%).

36. Major surgical procedure (as defined by the Investigator) within 42 days prior tostudy inclusion.

37. A history of severe allergy or intolerance to contrast agents, narcotics, sedativesor atropine that cannot be managed medically.

38. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients that cannot be managed medically.

39. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis testing inline 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.

40. Receipt of live attenuated vaccine within 30 days prior to the first dose ofdurvalumab and/or tremelimumab. Note: patients, if enrolled, should not receive livevaccine whilst receiving durvalumab and/or tremelimumab and up to 30 days after thelast dose of durvalumab and/or tremelimumab.

41. Female patients who are pregnant or breastfeeding and who do not want to stopbreastfeeding. Male or female patients of reproductive potential who are not willingto employ any effective birth control method from screening and for at least 90 daysafter TheraSphere administration, 90 days after the last dose of durvalumab, and 6months after the last dose of tremelimumab.

42. Unstable chronic disease or evidence of any disease or condition that would placethe patient at undue risk and preclude safe use of TheraSphere, durvalumab andtremelimumab treatment as deemed by the site principal investigator.

43. Patients who are not able to follow the TheraSphere, durvalumab or tremelimumabtreatment requirements. For France Patients Only

44. Persons deprived of their liberty by a judicial or administrative decision, personssubject to psychiatric care under articles L. 3212-1 and L. 3213-1 who are notcovered by the provisions of Article L. 1121-8 and persons admitted to a health orsocial establishment for purposes other than research, including:

45. Pregnant, parturient, breast-feeding women (see also inclusion criterion 16 andexclusion criterion 27)

46. Minors (see also inclusion criterion 1)

47. Persons receiving psychiatric treatment (see also exclusion criteria 28)

48. Persons admitted to a health or social establishment for purposes other thanresearch

49. Person of full age under curatorship

50. Adult subject to a mandate for future protection, a family authorization, or aguardianship measure

51. Person not affiliated or not beneficiary of a social security scheme