Cabozantinib in Patients With Hepatocellular Carcinoma (ACTION)

Inclusion Criteria: 1. Hepatocellular Carcinoma (HCC) diagnosed according to criteria of American Association for the Study of Liver Diseases (AASLD) definition in 2010. 2. Intolerant to sorafenib according to RESORCE trial definition or patients who received treatment different to sorafenib as first-Line treatment. 3. The subject has disease that is not amenable to a curative treatment approach (eg, transplant, surgery, radiofrequency ablation) 4. Recovery to ≤ Grade 1 according to (CTCAE) v.5.0. from toxicities related to any prior treatments, unless the adverse events are clinically non-significant and/or stable on supportive therapy 5. Respect the 15 days of first-line treatment washout before starting cabozantinib 6. Age ≥ 18 years old on the day of consent 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 8. Adequate hematologic function, based upon meeting the following laboratory criteria within 7 days before starting therapy: 1. absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 10\*9/L) 2. platelets ≥ 60,000/mm3 (≥ 60 x 10\*9/L) 3. hemoglobin ≥ 8 g/dL (≥ 80 g/L) 9. Adequate renal function, based upon meeting the following laboratory criteria within 7 days before starting therapy: 1. Serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40 mL/min (using the Cockcroft-Gault equation) AND 2. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein \< 1 g 10. Child-Pugh Score of A 11. Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L) within 7 days before starting therapy 12. Serum albumin ≥ 2.8 g/dL (≥28 g/L) within 7 days before starting therapy 13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 upper limit of normal (ULN) within 7 days before starting therapy 14. Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before starting therapy (if HbA1c results are unavailable \[eg, hemoglobin variant\], a fasting serum glucose ≤ 160 mg/dL) 15. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection 16. Capable of understanding and complying with the protocol requirements and signed informed consent 17. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment 18. Female subjects of childbearing potential must not be pregnant at screening. 19. Subjects must consent to perform a tumor liver biopsy within 4 weeks before starting cabozantinib, allowing the acquisition of a tumor sample for performance of correlative studies. Exclusion Criteria: 1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma 2. Radiation therapy (eg, I-131 or Y-90) within 4 weeks (2 weeks for radiation for bone metastases or radionuclide treatment within 6 weeks of starting therapy) (subject is excluded if there are any clinically relevant ongoing complications from prior radiation therapy) 3. Prior cabozantinib treatment 4. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before starting therapy. Eligible subjects must be without corticosteroid treatment at the time of starting therapy. 5. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, low molecular weight heparin (LMWH), thrombin or coagulation factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose 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 hypertension defined as sustained BP \> 150 mm Hg systolic, or 100 mm Hg diastolic despite optimal antihypertensive treatment iii. Stroke (including TIA), myocardial infarction, or another ischemic event within 6 months before starting therapy iv. Thromboembolic event within 3 months before starting therapy. Subjects with thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumor are eligible b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before starting therapy iii. Note: Complete healing of an intra-abdominal abscess must be confirmed prior to starting therapy c. Major surgery within 2 months before starting therapy. Complete healing from major surgery must have occurred 1 month before starting therapy. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before starting therapy. Subjects with clinically relevant complications from prior surgery are not eligible d. Cavitating pulmonary lesion(s) or endobronchial disease e. Lesion invading a major blood vessel including, but not limited to: pulmonary artery, or aorta. Subjects with lesions invading the portal vasculature are eligible. f. Clinically significant bleeding risk including the following within 3 months of starting therapy: hematuria, hematemesis, hemoptysis of \>0.5 teaspoon (\>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors g. Other clinically significant disorders such as: i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS)-related illness. Subjects with active hepatitis virus infection controlled with antiviral therapy are eligible. ii. Serious non-healing wound/ulcer/bone fracture iii. Malabsorption syndrome iv. Uncompensated/symptomatic hypothyroidism v. Requirement for hemodialysis or peritoneal dialysis vi. History of solid organ transplantation 7. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding. Subjects treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible. 8. Moderate or severe ascites. Note that controlled ascites with stable dose of diuretics in the last month is allowed. 9. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms within 7 days before starting therapy 10. Inability to swallow tablets 11. Previously identified allergy or hypersensitivity to components of the study treatment formulations 12. Pregnant or lactating females 13. Diagnosis of another malignancy within 2 years before starting therapy, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy 14. History of allergy to study drug components. 15. Prisoners or subjects who are involuntarily incarcerated 16. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg. infectious disease) illness 17. Inability to comply with restrictions and prohibited activities/treatments.