The HCC patient-journey study: a prospective, adaptive, master protocol, to assess the value of the available sequences of treatment for patients with advanced hepatocellular carcinoma. The Journey of liver cancer patient - J-LI

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• Psychiatric illness making informed consent impossible 2. Patients with previous malignancies if not curatively treated or anticancer treatment is ongoing (i.e. patients with no evidence of disease and not receiving any treatment for the previous cancer are eligible) All J-LI RCTs 3. Any concurrent investigational product or other anticancer treatment. 4. Active infection, with the exception of hepatitis C. Hepatitis B infection must be under control with appropriate antiviral therapy. 5. Symptomatic brain metastases or spinal cord compression 6. Leptomeningeal carcinomatosis 7. Clinically significant cardiovascular disease, including: a. Myocardial infarction or unstable angina pectoris within 6 months prior to first study treatment b. New York Heart Association (NYHA) grade II or higher congestive heart failure (CHF) c. Uncontrolled hypertension d. serious cardiac arrhythmia requiring medication (except atrial fibrillation or paroxysmal supraventricular tachycardia) e. Peripheral vascular disease > grade 3 (i.e. symptomatic and interfering with activities of daily living requiring repair or revision) f. QTc ≥470 ms calculated using Fredericia’s correction. 8. Known hypersensitivity to any of the study drugs or excipients. 9. Any other medical condition, laboratory abnormality, or social circumstance that may interfere with study participation or increase patient’s risk. 10. Radiotherapy to brain or chest or >30% bone marrow within 4 weeks prior to first dose of study treatment (2 weeks for palliative radiation). 11. Major surgery within 28 days prior to the first dose of study drugs (complete wound healing required). 12. Breastfeeding women 13. Active bleeding, coagulopathy, or medical condition associated with high bleeding risk. 14. Esophageal varices not adequately treated For J-LI1 RCT 15. Prior medical treatment for advanced HCC 16. Use of immunosuppressive medication within 14 days before the first dose of study treatment (physiologic corticosteroid doses ≤10 mg/day of prednisone equivalent allowed). 17. Active or documented autoimmune disease within past 2 years (except vitiligo, Graves’ disease, or psoriasis not requiring systemic treatment). 18. Active or documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) 19. History of allogeneic organ transplant 20. Active primary immunodeficiency 21. Live attenuated vaccine within 30 days prior to the first dose of study drugs. For J-LI2 RCT 22. Inability to swallow oral medication or malabsorption condition affecting drug absorption

• Locally advanced or metastatic and/or unresectable HCC. 2. Child-Pugh class A 3. Age ≥ 18 years 4. Any gender 5. Written informed consent obtained from the subject prior to performing any protocol-related procedures 6. Adeguate contraceptives measures: • Women of childbearing potential (WOCBP) must agree to use one highly effective method of contraception, and their male partners must use a condom. • Male subjects must agree to use a condom during sexual intercourse and ensure their partner uses an additional effective contraceptive method if she is of childbearing potential, unless confirmed to be azoospermic. Contraceptive measures must begin at the time of signing informed consent and continue during treatment and after the last dose of the study drug for the period specified in the Summary of Product Characteristics (SmPC) of each study drug. All J-LI RCTs 7. ECOG performance status 0 to 2 8. Life expectancy > 3 months 9. Adequate renal and hepatic function, defined as: • Total serum bilirubin ≤ 1.5 institutional ULN. • AST and/or ALT ≤ 5 x ULN • Serum creatinine ≤ 1.5 x ULN for the institution (or calculated creatinine clearance ≥ 40 mL/min/1.73 m2). 10. Adequate bone marrow function, defined as: • Haemoglobin >9.0 g/dL • Absolute neutrophils count (ANC) > 1.5 x 10^9/L (> 1500 per mm3) • Platelet count >75 x 10^9/L(>75,000 per mm3) for J-LI1. >50 x 10^9/L(>50,000 per mm3) for J-LI2. 11. Adequate coagulation function defined as INR or PT aPTT/PTT ≤1.5 × ULN unless the participant is receiving anticoagulant therapy and values are within the therapeutic range according to clinical practice. 12. WOCBP (those who have not been surgically sterilized or have not been free from menses for ≥1 year) must have a negative urine or serum pregnancy test at study screening visit 13. Written informed consent specific for participation in the in the J-LI1 or J-LI2 study obtained prior to performing any protocol-related procedures J-LI2 RCT 14. Radiologically confirmed disease progression (PD) after a previous first-line immunotherapy-based treatment for advanced HCC