Immunotherapy for Advanced Liver Cancer

Inclusion Criteria:

1. Males and females who are at least 18 years of age at time of enrollment

2. Histologically or cytologically documented advanced HCC (BCLC stage C) disease atdiagnosis.

3. No prior treatment for BCLC class C disease.

4. Child-Pugh Class A or subset of Child-Pugh Class B

5. Performance status: ECOG < 2 with no deterioration over the previous 2 weeks

6. With or without positive HBV and/or HCV

7. With or without extrahepatic disease and with or without macrovascular invasion

8. Measurable enhancing disease in liver with at least one target lesion evaluable bymRECIST

9. Adequate hematological, liver and renal function as assessed by the following:

• Hemoglobin > 10.0 g/dl

• Platelet count > 75,000/μl

• ALT and AST < 5.0 x ULN

• Serum creatinine < 1.5

10. Women of child-bearing potential: negative pregnancy test

11. Patients of child producing potential: usage of contraception or avoidance ofpregnancy measures while enrolled on study

12. Ability to understand the study, its inherent risks, side effects and potentialbenefits and ability to give written informed consent to participate

Exclusion Criteria:

1. Any prior cancer diagnosis (other than cured basal cell carcinoma, head and neckcarcinoma in-situ, or superficial Ta, Tis, T1 bladder cancer) or concurrent cancerhistologically different than HCC (e.g., cholangiocarcinoma).

2. Child-Pugh liver function combined score >9 (Class C or Class D)

3. Moderate uncontrolled or severe ascites (+3 on Child-Pugh calculator)

4. Clinical symptoms of hepatic decompensation or presence of hepatic encephalopathy

5. Severe stomach/esophageal varices requiring interventional treatment.

6. Unable to tolerate radiological contrast dye

7. Any prior experimental, approved or off-label treatment for HCC (includinglevantinib, nivolumab, duvalumab, tremelimumab, brivananib, cabozantinib orramucircumab) or any approved or experimental procedures such as surgery, radiationor ablation.

8. Enrollment in any previous clinical trial for HCC

9. Any history of autoimmune disorder (type I, insulin-dependent diabetes allowed)

10. History of COPD or oxygen saturation <92% at room air

11. Any clinical condition requiring systemic steroids (inhaled steroids allowed) or anycurrent immunosuppressive therapy or anti-epileptic drug therapy.

12. Known history of HIV infection

13. Clinically significant gastrointestinal bleeding within 30 days prior to study entry

14. History of cardiac disease: congestive heart failure > NYHA class 2; cardiacarrhythmias requiring anti-arrhythmic therapy (beta blockers or Digoxin arepermitted)

15. Uncontrolled hypertension (SBP >150 or DBP>90).

16. Active clinically serious infections (> grade 2 CTCAE version 5.0)

17. History of organ transplant or tissue allograft

18. Uncontrolled concurrent serious medical or psychiatric illness

19. Clinically apparent central nervous system metastases or carcinomatous meningitis

20. History of drug abuse or current alcohol abuse

21. History of blood transfusion reactions

22. Pregnant or lactating women