Regorafenib Followed by Nivolumab in Patients With Hepatocellular Carcinoma (GOING)

Inclusion Criteria:

1. Male or female subjects 18 years of age or older.

2. HCC diagnosed according to American Association for the Study of Liver Diseases (AASLD) guideline.

3. Presence of a naïve target lesion.

4. Adequate liver function

5. Performance status 0-1

6. Controlled arterial hypertension and/or stable peripheral vascular disease

7. Adequate hematologic profile

8. Adequate renal function

9. All but first-line-related dermatologic adverse events must be grade I according to Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Early dermatologic adverse events related to sorafenib must be resolved before starting regorafenib.

10. Radiological tumor progression to first-line treatment within the 2 months of inclusion in the study.

Exclusion Criteria:

1. Myocardial infarction in the last year or active ischemic heart disease

2. Acute variceal bleeding in the last month

3. Severe peripheral arterial disease

4. Cardiac arrhythmia under treatment with drugs different from beta-blockers or digoxin

5. Uncontrolled ascites

6. Encephalopathy

7. Unfeasibility to fulfill the follow-up schedule

8. Co-infection with hepatitis B (HBV) and C (HCV)

9. Prior malignancy active within the previous 3 years

10. Subjects with any active autoimmune disease or history of known or suspected autoimmune disease

11. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

12. Known active drug or alcohol abuse

13. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-Lymphocyte Antigen 4 antibody (anti-CTLA-4 antibody)

14. Prior organ allograft or allogeneic bone marrow transplantation

15. All but dermatologic toxicities attributed to first-line treatment must have resolved to Grade 1 (NCI CTCAE version 5) or baseline before administration of study drug. Subjects with toxicities attributed to first-line treatment therapy that are not expected to resolve and result in long-lasting sequelae are not permitted. Neuropathy must have resolved to Grade 2 (NCI CTCAE version 5). Dermatologic toxicities must be resolved.

16. Active bacterial or fungal infections requiring systemic treatment within 7 days.

17. Use of other investigational drugs (drugs not marketed for any indication) within 28 days or at least 5 half-lives (whichever is longer) before study drug administration.

18. Known or underlying medical conditions that, in the Investigator's opinion, would make the administration of the study drug hazardous to the subjects or obscure the interpretation of toxicity determination or adverse events.

19. Subjects with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study drug administration.

20. Laboratory evidence of any underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events

21. History of severe hypersensitivity reactions to other monoclonal antibodies.

22. History of allergy to study drug components.

23. Women who are pregnant or breastfeeding.

24. Women with a positive pregnancy test at enrollment or prior to administration of study medication.

25. Prisoners or subjects who are involuntarily incarcerated.

26. Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness

27. Inability to comply with restrictions and prohibited activities/treatments.