Atezolizumab and Bevacizumab With Proton Radiotherapy for Unresectable Hepatocellular Carcinoma

Prior treatment

• 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
• Presence of distant metastases that cannot be encompassed by proton radiotherapy
• 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
• 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.

Other illness

• Prior invasive malignancy unless disease free for a minimum of 2 years
• Untreated active hepatitis B or hepatitis C
• 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.

Other

• Moderate to severe or intractable ascites
• Untreated or incomplete treated esophageal or gastric varices
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

• 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