Inclusion Criteria
1. Ability of participant OR Legally Authorized Representative (LAR) to understand this study, and participant or LAR willingness to sign a written informed consent .
2. Males and females age ≥ 18 years.
3. ECOG Performance Status 0 - 1
4. Histologically confirmed hepatocellular carcinoma (HCC) or mixed HCC and cholangiocarcinoma either locally advanced or metastatic.
5. Not a candidate for surgical resection, or transplant
6. Child Pugh A - B7 liver function scale classification 14 days prior to entry.
7. Unresectable, locally-advanced or metastatic hepatocellular carcinoma. Meets normal liver and adjacent organ radiation dose constraints, which usually corresponds to tumor sizes 4 - 12 cm in diameter. Tumors that are larger than 12cm are permitted provided radiation dose constraints to adjacent normal tissue are met per radiation dose constraint table
8. Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to initiating study intervention. Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence, or to use an acceptable form of contraception for the duration of study participation, and for at least 12 months following completion of therapy. Men of child-bearing potential must agree not to donate sperm while on this study and for at least 12 months after their last study treatment.
Adequate organ function, defined as follows: Result Date
9. Hemoglobin ≥8 g/dL (The use of transfusion is acceptable)
10. Absolute Neutrophil Count \> 1.0 K/UL
11. Platelets \> 50 K/UL
12. AST and ALT \< 6 times upper limit of normal (ULN)
13. Albumin \>2.9g/dl
14. Prothrombin/INR \< 1.7
15. Creatinine \< 1.5x ULN or creatinine clearance \> 60 mL/min
16. Total Bilirubin \< 3.0
17. Esophageal varices, if present, must be \< Grade 2 and can not have had bleeding in the last 6 months. If clinically indicated, a standard care Esophageal Gastric Duodenoscopy (EGD) is recommended to rule out uncontrolled esophageal varices. NOTE: EGD is not required for enrollment.
18. Documented virology status of hepatitis, as confirmed by HBV / HCV serology test. Patients with known hepatitis are allowed on this study provided they meet all other eligibility criteria. Concomittant therapy for hepatitis is permitted at the principal investigator's discretion.
19. No known history or suspected human immunodeficiency virus (HIV). Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ (350) cells/microliter, and no known detectable viral load, at the time of study entry. Note also that HIV testing is not required for eligibility for this protocol.
Exclusion Criteria
1. Hepatocelluar carcinoma (HCC) or other mixed subtype (fibrolamellar HCC, or sarcomatoid HCC) amenable to curative surgery or transplant
2. Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with study requirements.
3. Is pregnant or breastfeeding.
4. Prior Abdominal radiation, including prior arterial Yttrium therapy.
5. History of autoimmune disease.
6. Current use of immunosuppressive drugs, such as corticosteroids, or TNF-alpha blockers.
7. Concurrent active secondary malignancy, excluding indolent cancers such as treated cutaneous malignancies or treated chronic lymphocytic leukemia, or prior cancers now in remission for 3 years or longer.
8. Direct tumor extension into the stomach or duodenum. Small bowel or large bowel or untreated esophageal varices greater than Grade 3 are not allowed.
9. Measureable common or main branch biliary duct involvement with HCC.
10. Severe active co-morbidities
11. All participants: Participants should not donate blood or blood components while participating in this study and through 180 days after the last study dose.
12. Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before first dose. Patients with clinically relevant ongoing complications from prior surgery are not eligible.
13. History of organ transplantation.
14. Uncontrolled hypertension despite optimal antihypertensive treatment in the opinion of the principal investigator.
15. Uncontrollable ascites or pleural effusion.
16. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 8 weeks before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose.
17. Active autoimmune disease (active defined as having autoimmune disease related symptoms and detectable autoantibodies) that has required systemic treatment in the past 2 years.
18. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drugs. Except Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection), Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent, Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
19. Clinically significant gross hematuria, hematemesis, or hemoptysis of \>0.5 tsp (2.5ml) of red blood, or other history of grade 3 significant bleeding within 8 weeks.
22\. Cholangiocarcinoma (intra/extra-hepatic).
