Regorafenib After Progression on Atezolizumab Plus Bevacizumab in Advanced HCC

Inclusion Criteria:

1. Diagnosis of HCC according to AASLD guidelines
2. Disease that is not amenable to a curative treatment (e.g. surgery, transplant,radiofrequency ablation)
3. Prior treatment with atezolizumab plus bevacizumab combination as 1st line treatmentfor unresectable HCC
4. Progression after atezolizumab plus bevacizumab treatment, The duration ofatezolizumab plus bevacizumab must be 2 consecutive treatment cycles or more
5. Recovery to ≤ Grade 1 from toxicities related to any prior treatments, unless theadverse events are clinically non-significant and/or stable on supportive therapy
6. Life expectancy of 12 weeks or longer
7. Age ≥ 19 years old
8. ECOG performance status of 0, 1
9. Adequate hematological function
10. Absolute neutrophil count (ANC) ≥ 1.5 x109/L
11. Platelets ≥ 75 x 109/L
12. Hemoglobin ≥ 10 g/dL
13. Adequate renal function
14. serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40 mL/min (using the Cockroft-Gault equation) AND
15. urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hoururine protein < 1 g
16. Child-Pugh Score of 5 or 6
17. Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L)
18. Serum albumin > 2 g/dL (> 20 g/L)
19. Alanine aminotransferase (ALT) < 3.0 upper limit of normal (ULN)
20. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection
21. Capable of understanding and complying with the protocol requirements and signedinformed consent
22. Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 4 months after the last dose of study treatment
23. Female subjects of childbearing potential must not be pregnant at screening.

Exclusion Criteria:

1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
2. Prior regorafenib treatment
3. Prior systemic treatment for HCC, except for atezolizumab plus bevacizumab (i.e.regorafenib must be 2nd line systemic treatment)
4. Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 3 monthsbefore randomization.
5. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such aswarfarin or warfarin-related agents, low molecular weight heparin (LMWH), thrombin orcoagulation factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Lowdose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and low dose LMWH are permitted.
6. The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions: a. Cardiovascular disorders including i. Symptomatic congestive heart failure,unstable angina pectoris, or serious cardiac arrhythmias ii. Uncontrolled hypertensiondefined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimalantihypertensive treatment iii. Stroke (including TIA), myocardial infarction, orother ischemic event within 6 months iv. Thromboembolic event within 3 months.Subjects with thromboses of portal/hepatic vasculature attributed to underlying liverdisease and/or liver tumour are eligible b. Gastrointestinal (GI) disorders includingthose associated with a high risk of perforation or fistula formation/bleeding: i.Tumours invading the GI tract, active peptic ulcer disease, inflammatory boweldisease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acutepancreatitis or acute obstruction of the pancreatic duct or common bile duct, orgastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction,intra-abdominal abscess within 6 months
7. Major surgery within 2 months before randomization. Complete healing from majorsurgery must have occurred 1 month before randomization. Complete healing from minorsurgery (eg, simple excision, tooth extraction) must have occurred at least 7 daysbefore registration. Subjects with clinically relevant co d. Cavitating pulmonarylesion(s) or endobronchial disease
8. Lesion invading a major blood vessel (eg, pulmonary artery or aorta)
9. Clinically significant bleeding risk including the following within 28 days ofregistration: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of redblood, or other signs indicative of pulmonary hemorrhage, or history of othersignificant bleeding if not due to reversible external factors
10. Gastric or esophageal varices that require interventional treatment within 28 daysprior to registration. Prophylaxis with pharmacologic therapy (e.g. non-selective betablocker) is permitted.
11. Moderate or severe ascites (Radiologically detected but clinically insignificantascites is allowed)
12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 21days of registration

• If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If theaverage of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meetseligibility in this regard.

13. Previously identified allergy or hypersensitivity to components of the study treatmentformulations
14. Pregnant or lactating females
15. Diagnosis of another malignancy within 2 years before randomization, except forsuperficial skin cancers, or localized, low-grade tumors deemed cured and not treatedwith systemic therapy
16. Other clinically significant disorders that are judged by investigators to beunsuitable for the clinical trial