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 HCC with 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. (All parameters without transfusion within 3 months).
5. Age \> 18 years.

Exclusion Criteria:

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

   1. Hemoglobin \< 90 g/L
   2. Platelet count \< 75 x 109/L without transfusion
   3. INR \>1.25
   4. Serum creatinine \> 1.5 x ULN
   5. Urine dipstick for proteinuria \> 2 (unless a 24-hour urine collection demonstrates \< 1.5 g of protein in 24 hours.
2. Previous therapy for HCC:

   1. Systemic therapy, surgery or radiation therapy,
   2. Local therapy to the liver (e.g., ablation or embolization) within 28 days prior to randomization.
3. ECOG performance status \> 2 (see Appendix IV).
4. Non-healing wound, skin ulcers, or incompletely healed bone fracture.
5. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to planned start of study therapy.
6. History of bleeding from esophageal and/or gastric varices or high risk of bleeding from varices seen on endoscopy (normal EGD required within 6 months of randomization).
7. History of GI perforation, abdominal fistulae, or intra-abdominal abscess.
8. Significant cardiovascular disease:

   1. New York Heart Association cardiac disease (Class II or greater),
   2. Myocardial infarction, unstable angina or cerebrovascular accident within past 3 months,
   3. Unstable arrhythmia,
   4. Poorly controlled arterial hypertension (defined as systolic blood pressure (BP) \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg) based on an average of \> 3 BP readings on \> 2 sessions), or prior history of hypertensive crisis or hypertensive encephalopathy,
   5. Aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis within 6 months prior to randomization
9. Known contraindication to Bevacizumab or Immune Checkpoint Inhibitor (ICI): Active or history of autoimmune disease or immune deficiency, 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, autoimmune hypophysitis, or autoimmune pancreatitis. Includes known hypersensitivity to any component of Bevacizumab; Chinese hamster ovary cell products or other recombinant human or humanized antibodies. Known hypersensitivity to Atezolizumab or any of the excipients. (Note: Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone and those with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study).
10. Known history of (Human immunodeficiency virus (HIV), HBV and HCV co-infection). For patients with active HBV: HBV DNA \<500IU/mL obtained within 28 days prior to randomization 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.
11. 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.
12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis.
13. Active tuberculosis.
14. Prior allogeneic stem cell or solid organ transplantation.
15. 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.
16. Recent administration of live vaccine.
17. History of malignancy other than HCC within 5 years prior to screening, with the exception of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ of breast, or Stage I uterine cancer.
18. Treatment with strong CYP3A4 inducers within 14 days prior to randomization.
19. Treatment with an immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 14 days prior to randomization, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: a) patients 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), or b) patients 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.
20. Current or recent (within 7 days of randomization) use of aspirin (325mg/day), dipyramidole, ticlopidine, clopidogrel, or cilostazol, Vitamin K antagonists, direct oral anticoagulants (DOACs), LMWH.
21. Recent history (within 4 weeks) of hemoptysis.
22. History of TIA, CVA, or any arterial thrombotic event within 12 months before randomization.
23. Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI CTCAE and history of hypomagnesemia.
24. Known severe allergic reaction to contrast (e.g., anaphylaxis).
25. Pregnancy or lactating women.
26. Inability to provide informed consent.