Neoadjuvant Combination of Atezolizumab/Bevacizumab Versus Neoadjuvant Radiation Therapy

Inclusion Criteria:

1. Biopsy proven solitary HCC without biliary invasion, or metastases,

2. PVTT involving the portal vein branches: Vp1-Vp3 (Japanese Classification for HCCwith PVTT, see Appendix II),

3. <10 cm maximal diameter on CT or MRI,

4. Child-Pugh Class A (see Appendix III), within 14 days prior to randomization. (Allparameters without transfusion within 3 months).

5. Age > 18 years.

Exclusion Criteria:

1. Abnormal laboratory parameters (within 14 days of randomization):

2. Hemoglobin < 90 g/L

3. Platelet count < 75 x 109/L without transfusion

4. INR >1.25

5. Serum creatinine > 1.5 x ULN

6. Urine dipstick for proteinuria > 2 (unless a 24-hour urine collectiondemonstrates < 1.5 g of protein in 24 hours.

7. Previous therapy for HCC:

8. Systemic therapy, surgery or radiation therapy,

9. Local therapy to the liver (e.g., ablation or embolization) within 28 daysprior to randomization.

10. ECOG performance status > 2 (see Appendix IV).

11. Non-healing wound, skin ulcers, or incompletely healed bone fracture.

12. Major surgical procedure, open biopsy, or significant traumatic injury within 28days prior to planned start of study therapy.

13. History of bleeding from esophageal and/or gastric varices or high risk of bleedingfrom varices seen on endoscopy (normal EGD required within 6 months ofrandomization).

14. History of GI perforation, abdominal fistulae, or intra-abdominal abscess.

15. Significant cardiovascular disease:

16. New York Heart Association cardiac disease (Class II or greater),

17. Myocardial infarction, unstable angina or cerebrovascular accident within past 3 months,

18. Unstable arrhythmia,

19. Poorly controlled arterial hypertension (defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic blood pressure > 100 mmHg) based on an averageof > 3 BP readings on > 2 sessions), or prior history of hypertensive crisis orhypertensive encephalopathy,

20. Aortic aneurysm requiring surgical repair or recent peripheral arterialthrombosis within 6 months prior to randomization

21. Known contraindication to Bevacizumab or Immune Checkpoint Inhibitor (ICI): Activeor history of autoimmune disease or immune deficiency, including, but not limited tomyasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibodysyndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, ormultiple sclerosis, autoimmune hypophysitis, or autoimmune pancreatitis. Includesknown hypersensitivity to any component of Bevacizumab; Chinese hamster ovary cellproducts or other recombinant human or humanized antibodies. Known hypersensitivityto Atezolizumab or any of the excipients. (Note: Patients with a history ofautoimmune-related hypothyroidism who are on thyroid-replacement hormone and thosewith controlled Type 1 diabetes mellitus who are on an insulin regimen are eligiblefor the study).

22. Known history of (Human immunodeficiency virus (HIV), HBV and HCV co-infection). Forpatients with active HBV: HBV DNA <500IU/mL obtained within 28 days prior torandomization 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 treatmentfor the length of the study.

23. Severe infection within 4 weeks prior to initiation of study treatment, including,but not limited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia.

24. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis.

25. Active tuberculosis.

26. Prior allogeneic stem cell or solid organ transplantation.

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

28. Recent administration of live vaccine.

29. History of malignancy other than HCC within 5 years prior to screening, with theexception of adequately treated carcinoma in situ of the cervix, non-melanoma skincarcinoma, localized prostate cancer, ductal carcinoma in situ of breast, or Stage Iuterine cancer.

30. Treatment with strong CYP3A4 inducers within 14 days prior to randomization.

31. Treatment with an immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF-α agents) within 14 days prior to randomization, or anticipation of needfor systemic immunosuppressive medication during study treatment, with the followingexceptions: a) patients who received acute, low-dose systemic immunosuppressantmedication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy), or b) patients who receivedmineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructivepulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatichypotension or adrenal insufficiency.

32. Current or recent (within 7 days of randomization) use of aspirin (325mg/day),dipyramidole, ticlopidine, clopidogrel, or cilostazol, Vitamin K antagonists, directoral anticoagulants (DOACs), LMWH.

33. Recent history (within 4 weeks) of hemoptysis.

34. History of TIA, CVA, or any arterial thrombotic event within 12 months beforerandomization.

35. Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCICTCAE and history of hypomagnesemia.

36. Known severe allergic reaction to contrast (e.g., anaphylaxis).

37. Pregnancy or lactating women.

38. Inability to provide informed consent.