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

Inclusion Criteria: 1. Male or female subjects 18 years of age or older. 2. Diagnosis of HCC based on histology or non-invasive criteria if the patients are cirrhotic according to AASLD guidelines. 3. Adequate liver function 4. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 1. 5. Adequate hematologic profile 6. Adequate renal function 7. All but sorafenib-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 first-line treatment must be resolved before starting regorafenib. 8. Patients with Hepatocellular Carcinoma * Who develop radiological tumor progression on sorafenib treatment within the 2 months of inclusion in the study and either: 1. who are candidates to regorafenib treatment according to the definition in the RESORCE trial or 2. who tolerated between 200 and 400 mg of sorafenib for at least 30 days and who did not experience adverse events of grade 3 or more (excluding dermatologic adverse events)(Cohort A). * After discontinuation of atezolizuamab in combination with bevacizumab because of tumor progression or treatment related toxicity (Cohort B). Note that patients should have received at least 2 doses of atezolizumab in combination with bevacizumab. 9. All subjects must have at least one measurable lesion by RECIST 1.1 criteria. Lesions previously treated by percutaneous ablation or TACE must not be considered as target lesion, only naïve target lesions. 10. Subjects may be non-infected or have active chronic HCV or HBV infection. 11. Subjects must consent to perform 2 hepatic or extra-hepatic tumor biopsies, the first one within 4 weeks before starting regorafenib (this biopsy should be performed at least 5-7 days after the last dose of sorafenib and 21 days after the last dose of atezolizumab in combination with bevacizumab) and the second-one before starting the combination phase (regorafenib plus nivolumab) of the study, allowing the acquisition of a tumor sample for performance of correlative studies. 12. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug. 13. Women must not be breastfeeding. 14. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 5 half-lives of study drug plus 90 days for a total of 31 weeks post-treatment completion 15. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. 16. WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug plus 5 half-lives of study drug plus 30 days for a total of 23 weeks post treatment completion. Exclusion Criteria: 1. Subjects with myocardial infarction in the last year or active ischemic heart disease 2. Subjects with any history of clinically meaningful variceal bleeding within the last three months. 3. Subjects with severe peripheral arterial disease 4. Subjects with cardiac arrhythmia under treatment with drugs different from beta-blockers or digoxin. 5. Subjects with clinically meaningful ascites defined as ascites requiring non-pharmacologic intervention within 6 months prior to the first scheduled dose. 6. Subjects with any history of encephalopathy within the last 12 months or requirement for medications to prevent or control encephalopathy. 7. Unfeasibility to fulfill the follow-up schedule 8. Co-infection with hepatitis B and C. 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) defining opportunistic infection within the last year, or a current CD4 count \< 350 cells/μL. Patients with HIV infection are eligible if : 1. They do not have another active viral infection. 2. They have received antiretroviral therapy (ART\*) for at least 4 weeks prior to randomization, as clinically indicated. 3. They continue on ART as clinically indicated while enrolled on study. 4. CD4 counts and viral load are monitored per standard of care by a local health care provider. (\*) The ART regimen includes drugs that are permitted according to protocol. An evaluation by the infectious disease specialist should be provided to the Medical Monitor (MM) prior to the enrollment. 12. Known active drug or alcohol abuse. 13. Prior therapy with an anti-PD-1, anti-PD-L1 (other than atezolizumab), anti-PD-L2, anti-CD137, or anti-Cytotoxic T-Lymphocyte Antigen 4 antibody (anti-CTLA-4 antibody) 14. Prior monotherapy treatment with any tyrosine kinase inhibitor in first line other than sorafenib. 15. Prior organ allograft or allogeneic bone marrow transplantation 16. 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. 17. Active bacterial or fungal infections requiring systemic treatment within 7 days. 18. 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. 19. 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. 20. Subjects with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study drug administration. 21. 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 22. History of severe hypersensitivity reactions to other monoclonal antibodies or regorafenib. 23. History of allergy to study drug components. 24. WOCPB who are pregnant or breastfeeding. 25. Women with a positive pregnancy test at enrollment or prior to administration of study medication. 26. Prisoners or subjects who are involuntarily incarcerated. 27. Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness 28. Inability to comply with restrictions and prohibited activities/treatments. 29. Subjects in the Child-Pugh classes B≥7 points or C are not allowed to be recruited into this trial. 30. subjects with uncontrolled arterial hypertension. 31. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, low molecular weight heparin (LMWH), thrombin or coagulation factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel).