Atezolizumab and Bevacizumab With Proton Radiotherapy for Unresectable Hepatocellular Carcinoma

Inclusion Criteria:

* Participants must have diagnosis of HCC that is deemed unsuitable for surgical resection or transplant. Participants may have multiple lesions with a total maximal tumor dimension of \< 20 cm, and no one lesion \> 15 cm. Diagnosis should be confirmed by at least 1 criterion listed below:

  * Histologically or cytologically proven diagnosis of HCC.
  * Typical arterial enhancement and delayed washout on multiphasic CT or MRI.
* Age ≥18 years at the time of signing informed consent document.
* ECOG performance status 0-1.
* Barcelona Clinic Liver Cancer (BCLC) stages Intermediate (B) or Advanced (C).
* Child-Pugh score 5-6 liver function within 28 days of study registration.
* Documented virology status of hepatitis B virus (HBV), as confirmed by screening HBV serology test.
* Documented virology status of hepatitis C virus (HCV), as confirmed by screening HCV serology test.
* Ability to understand and the willingness to sign a written informed consent document
* Adequate bone marrow, liver, and renal function within 4 weeks before study registration

  * Hemoglobin ≥ 9.0 g/dL
  * Absolute neutrophil count (ANC) ≥ 1,000/mm3
  * Platelet count ≥ 50,000/μL
  * Total bilirubin \< 2.5 mg/dL
  * Serum albumin \>2.8 g/dL
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN)
  * Prothrombin time ≤ 6 seconds prolonged
  * Serum creatinine ≤ 1.5 mg/dL

Exclusion Criteria:

* Prior invasive malignancy unless disease free for a minimum of 2 years
* Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields
* Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time
* Untreated active hepatitis B or hepatitis C
* Moderate to severe or intractable ascites
* Presence of distant metastases that cannot be encompassed by proton radiotherapy
* Untreated or incomplete treated esophageal or gastric varices
* Severe, active co-morbidity, defined as follows:

  * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to registration
  * Myocardial infarction within the last 6 months prior to study entry
  * Acute bacterial or fungal infection requiring intravenous antibiotics within 28 days prior to study entry
  * A bleeding episode within 6 months prior to study entry due to any cause.
  * Thrombolytic therapy within 28 days prior to study entry.
  * Known bleeding or clotting disorder.
  * Uncontrolled psychotic disorder
* Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
* Prior solid organ transplantation.
* Prior or active autoimmune disease (AID) including autoimmune hepatitis, inflammatory bowel disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, and multiple sclerosis.
* Prior or active thrombotic or bleeding disorders, hemoptysis, cerebral vascular accident, significant cardiac disease (ischemic or congestive heart failure), or gastrointestinal perforation.
* Inability to treat all sites of disease by proton radiotherapy (such as extrahepatic metastases or massive liver tumors whereby the liver constraints \[ULV/SLV \>40%\] cannot be met for covering all sites of liver tumors using proton radiotherapy.)
* Known HIV infection.