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.