Cabozantinib in Patients With Hepatocellular Carcinoma (ACTION)

Inclusion Criteria

• Hepatocellular Carcinoma (HCC) diagnosed according to criteria of American Association for the Study of Liver Diseases (AASLD) definition in 2010.
• Intolerant to sorafenib according to RESORCE trial definition or patients who received treatment different to sorafenib as first-Line treatment.
• The subject has disease that is not amenable to a curative treatment approach (eg, transplant, surgery, radiofrequency ablation)
• 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
• Respect the 15 days of first-line treatment washout before starting cabozantinib
• Age ≥ 18 years old on the day of consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate hematologic function, based upon meeting the following laboratory criteria within 7 days before starting therapy:
• absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 10*9/L)
• platelets ≥ 60, 000/mm3 (≥ 60 x 10*9/L)
• hemoglobin ≥ 8 g/dL (≥ 80 g/L)
• Adequate renal function, based upon meeting the following laboratory criteria within 7 days before starting therapy:
• Serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40 mL/min (using the Cockcroft-Gault equation) AND
• Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein 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

• Subjects with untreated or incompletely tr