A Prospective Study to Evaluate the Safety and Efficacy of the Combination Therapy of Irpagratinib, Atezolizumab, and Bevacizumab in Patients With Hepatocellular Carcinoma

This is a phase 2, open-label study to evaluate the safety, tolerability and efficacy of Irpagratinib in combination with Atezolizumab and Bevacizumab in patients with advanced or unresectable HCC harboring FGF19 overexpression. This study composes two parts, a Safety Run-in part to evaluate safety and establish the dose of Irpagratinib for the triple combination, and an Expansion part to evaluate the preliminary efficacy and safety using Simon's two-stage design.

Inclusion Criteria: * 1.Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol. * 2.Male or female, aged ≥19 at the time of signing inform consent form. * 3.Patients must have histological or cytological confirmed advanced or unresectable HCC not amenable to curative surgical or loco-regional therapies. And patients must satisfy: 1. Provide archived tissue sample for FGF19 overexpression detection.For Safety-Run in and Expansion: the result of FGF19 overexpression lab testing must be positive as defined. Only tissue from primary lesion of liver is eligible. 2. Barcelona Clinic Liver Cancer (BCLC) stage B or C and Child-Pugh score 5\~6 without hepatic encephalopathy, no clinically apparent ascites or require medical intervention. 3. Have at least 1 target lesion (per RECIST v1.1). Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous injection, cryoablation, high-intensity focused ultrasound, transarterial (chemo) embolization, etc.) are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed per RECIST v1.1. * 4.ECOG performance status score 0-1 * 5.Life expectancy ≥ 3 months * 6.Adequate organ and hematologic function as indicated by the following screening assessments performed within 14 days prior to the first administration (without blood transfusion, or medication with stimulation factors or thrombopoietin receptor agonists (TPO-RAs) within 14 days before blood sample collection):a) Absolute neutrophil count (ANC) ≥1.0×109/Lb) Platelet count (PLT) ≥75×109/Lc) Hemoglobin (Hb) ≥85g/L (8.5g/dL)d) Total bilirubin (TBIL) ≤3×ULNe) Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5 ×ULNf) Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (Crcl) ≥50 mL/min based on Cockcroft-Gault formulag) For patients not receiving therapeutic anticoagulation: International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) ≤2×ULN.h) Urinalysis for proteinuria \ 470 ms \[average of three ECGs\], QTc interval corrected by Frederica's formula, QTcF=QT/RR0.33) at screening, and other ECG abnormalities with clinical significance by the judge of the investigator and affect the patient's safety assessment. * 26\. Left ventricle ejection fraction\103 copies/mL or following local clinical practice) or require concomitant anti-HCV therapy during the study. * 34\. Any other clinically significant comorbidities, such as respiratory, metabolic, congenital, endocrine or central nervous system disease, or any other medical conditions, mental disturbances or social determinants, which in the judgment of the Investigator, could compromise compliance with the protocol, interfere with the interpretation of study results, or predispose the patient to safety risks. Other Exclusions * 35\. History of allogeneic stem cell transplantation or organ transplantation. * 36\. History of hemoptysis (≥2.5mL of bright red blood per episode) within 1 month prior to initiation of study treatment. * 37\. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). * 38\. Current or recent (within 10 days prior to study treatment start) use of aspirin (\>325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol. * 39\. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anti-coagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose. * 40\. Prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an INR\