This is a phase II, multi-arm, Bayesian adaptive platform trial designed to efficiently evaluate novel therapies for advanced hepatocellular carcinoma (HCC) after first-line treatment failure. The study aims to rapidly identify the most effective investigational regimens and discover predictive biomarker signatures (from tumor tissue, blood, and imaging) to guide personalized second-line therapy.

This open-label, adaptive platform trial addresses the lack of effective second-line therapies for advanced HCC. Multiple experimental regimens will be evaluated against a common control arm. The study employs a Bayesian adaptive design. Patient randomization probabilities will favor regimens showing better interim efficacy (primary endpoint: objective response rate). Underperforming regimens will be dropped, and new ones may be added over time. A key objective is to identify predictive biomarker signatures. Baseline and on-treatment biomarker assessments (including tumor molecular profiling, ctDNA, and quantitative imaging features) will be analyzed to define patient subsets most likely to respond to each therapy. Regimens with a high predictive probability of success will graduate for further development. Those with low probability of benefit will be discontinued. This design enables rapid, biomarker-informed therapy screening for second-line HCC.

Inclusion Criteria:

• Written informed consent obtained.
• Age ≥ 18 years at time of study entry.
• Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/ cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic patients.
• Patients who have previously received first-line therapy with anti-PD-1/PD-L1 combined with anti-VEGF antibodies, or anti-PD-1/PD-L1 combined with TKI, or anti-PD-1/PD-L1 combined with anti-CTLA-4 antibodies and experienced disease progression; or disease recurrence within 6 months after completion of neoadjuvant/adjuvant immunotherapy.
• At least one measurable (per RECIST v1.1) target lesion that has not been previously treated with local therapy or, if the target lesion is within the field of previous local therapy, has subsequently progressed in accordance with RECIST v1.1.
• Child-Pugh scores 5-7, performance status (PS) ≤ 2 (ECOG scale).
• Subjects with chronic HBV infection must have HBV DNA viral load < 100 IU/mL at screening. In addition, they must be on antiviral therapy per regional standard of care guidelines prior to initiation of study therapy.
• Life expectancy of at least 12 weeks.
• Adequate blood count, liver-enzymes, and renal function: absolute neutrophil count ≥ 1,500/L, platelets ≥60 x103/L; Total bilirubin ≤ 3x upper normal limit; Aspartate Aminotransferase (SGOT), Alanine aminotransferase (SGPT) ≤ 5 x upper normal limit (ULN); International normalized ratio (INR) ≤1.25; Albumin ≥ 31 g/dL; Serum Creatinine ≤ 1.5 x institutional ULN or creatinine clearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault formula)
• Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment, adherence to contraceptive measures, scheduled visits and examinations including follow up.

Exclusion Criteria:

• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Patients on a liver transplantation list or with advanced liver disease.
• History of cardiac disease, including clinically significant gastrointestinal bleeding within 4 weeks prior to start of study treatment
• Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months Prior to the first dose of study drug with the exception of thrombosis of a segmental portal vein.
• Patients with second primary cancer, except adequately treated basal skin cancer or carcinoma in-situ of the cervix.
• Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is longer.
• Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study Treatment or interpretation of patient safety or study results, including but not limited to: a) history of interstitial lung disease b) Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection (i.e double infection) c) known acute or chronic pancreatitis d) active tuberculosis e) any other active infection (viral, fungal or bacterial) requiring systemic therapy f) history of allogeneic tissue/solid organ transplant g) diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment. h) Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Exceptions: Subjects with vitiligo, hypothyroidism, diabetes mellitus type I or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with Hashimoto thyroiditis, hypothyroidism stable on hormone replacement or psoriasis not requiring treatment are not excluded from the study. i) Live vaccine within 30 days prior to the first dose of treatment or during study treatment. j) History or clinical evidence of Central Nervous System (CNS) metastases Exceptions are: Subjects who have completed local therapy and who meet both of the following criteria: I. are asymptomatic and II. have no requirement for steroids 6 weeks prior to start of treatment. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS.
• Medication that is known to interfere with any of the agents applied in the trial.
• Any other efficacious cancer treatment except protocol specified treatment at study start.
• Patient has received any other investigational product within 28 days of study entry.
• Female subjects who are pregnant, breast-feeding or male/female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are: implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner]. Women of childbearing potential must have a negative pregnancy test (serum β-HCG) at screening.
• Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.