Optimization for Regorafenib in HCC

Inclusion Criteria: 1. Patients age ≥ 18 years. 2. Histological, cytological confirmation of hepatocellular carcinoma or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in patients with a confirmed diagnosis of cirrhosis. 3. Locally advanced or metastatic and/or unresectable HCC that is not amenable or progressed after curative surgical and/or locoregional therapies. 4. Patients who received one prior systemic treatment and for whom the treating physician has decided to treat with regorafenib. 5. Life expectancy of ≥ 3 months. 6. The following laboratory values obtained ≤ 7 days prior to randomization. * Absolute neutrophil count (ANC) \> 1500/mm3 * Platelet count \> 60,000/mm3 * Hemoglobin \> 9.0 g/dL * Albumin \> 2.7 gm/dL * Total bilirubin \< 2 mg/dl (Mildly elevated total bilirubin (\< 6 mg/dL) is allowed if Gilbert's syndrome is documented) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 5 x ULN * Serum creatinine ≤ 1.5 x ULN or creatinine clearance \> 50 mL/min (calculated using the Cockcroft-Gault formula) * INR/PTT ≤ 1.5 x ULN * Alkaline phosphatase limit ≤ 2.5 x ULN 7. At least one measurable (per RECIST 1.1) lesion. Patients who received prior local therapy (e.g., radiofrequency ablation or transarterial chemoembolization, 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 in accordance with RECIST 1.1. 8. Eastern Cooperative Oncology Group (ECOG) = 0 or 1 9. Negative serum pregnancy test done ≤ 7 days prior to randomization, for females of childbearing potential only. 10. Provide written informed consent. 11. Patients with a prior liver transplant may be included if they have no history of graft rejection within the previous 6 months and stable graft function. Exclusion Criteria: 1. Prior treatment with regorafenib. 2. Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to randomization. 3. Congestive heart failure \> New York Heart Association (NYHA) class 2. 4. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) or myocardial infarction less than 6 months prior to randomization. 5. Cardiac arrhythmias requiring anti-arrhythmic therapy. Note: beta blockers or digoxin are permitted. 6. Uncontrolled hypertension. (Systolic blood pressure \> 150 mmHg or diastolic pressure \> 90 mmHg despite optimal medical management). 7. History of or current pheochromocytoma. 8. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism ≤ 6 months prior to randomization. 9. Ongoing infection \> grade 2 NCI-CTCAE version 5.0. 10. Patients with seizure disorder requiring medication. 11. Symptomatic metastatic brain or meningeal tumors unless the patient is \> 6 months from definitive therapy, has a negative imaging study within 4 weeks of randomization and is clinically stable with respect to the tumor at the time of randomization. NOTE: Patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies). 12. History of organ allograft (including corneal transplant), except prior liver transplant. 13. Hepatic Encephalopathy requiring hospital admission within six (6) months prior to randomization. 14. Ascites requiring paracentesis within four (4) weeks of randomization. 15. Evidence or history of bleeding diathesis or any hemorrhage or bleeding event \> CTCAE grade 3 ≤4 weeks prior to randomization. 16. Non-healing wound, ulcer, or bone fracture. 17. Renal failure requiring hemo-or peritoneal dialysis. 18. Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results. 19. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation. 20. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent. 21. Persistent proteinuria of CTC Grade 3 or higher (\> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample). 22. Patients unable to swallow oral medications. 23. Any malabsorption conditions that will affect that absorption of regorafenib. 24. Unresolved toxicity greater than CTCAE (version 5.0) Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity ≤ Grade 2. 25. Pregnant or nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception because regorafenib is a chemotherapeutic agent that has known genotoxic, mutagenic, and teratogenic effects. NOTE: Men and women of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 2 months after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate. 26. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. 27. Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy. NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS)-related illness 29. Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE version 4.0 Grade 2 dyspnea). 30\. Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment (regorafenib, other agents being investigated in combination with regorafenib). 31\. Use of any herbal remedies known to have interference with liver or other major organ functions. Patients must notify the investigator of all herbal remedies used during the study.