Efficacy and Safety of Cabozantinib in Patients With Hepatocellular Carcinoma

Inclusion Criteria:

• Histological or cytological diagnosis of HCC (results of a previous biopsy will beaccepted)

• A baseline tumor tissue (newly obtained) available at screening is optional. Patientmust have a site of disease amenable to biopsy, and be a candidate for tumor biopsyaccording to the treating institution's guidelines and requirements for suchprocedure. Biopsy cannot be performed less than ten days before treatment start.

• The subject has disease that is not amenable to a locoregional treatment approach (eg,transplant, surgery, radiofrequency ablation, TACE)

• Patients must have documented disease progression following at least 1 and no morethan 2 prior systemic regimens for advanced disease (nonresectable or metastatic), thelast of which includes immune checkpoint inhibitors. Alternatively, eligible patientsmay have experienced an immune-related, requiring treatment discontinuation.

• Recovery to ≤ Grade 1 from toxicities related to any prior treatments, unless theadverse events are clinically not significant and/or stable on supportive therapy

• Age ≥ 18 years old on the day of consent

• ECOG performance status of 0 or 1 (See Appendix V)

• Adequate hematologic function, based upon meeting the following laboratory criteriawithin 7 days before treatment beginning:

• a. absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 109/L)

• b. platelets ≥ 60,000/mm3 (≥ 60 x 109/L)

• c. hemoglobin ≥ 8 g/dL (≥ 80 g/L)

• Adequate renal function, based upon meeting the following laboratory criteria: serumcreatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40mL/min (using the Cockroft-Gault equation: (140 - age) x weight (kg)/(serum creatinine × 72 [mg/dL]) for males. (For females multiply by 0.85)

• Child-Pugh Score of A (See Appendix IV)

• Total bilirubin ≤ 2 mg/dL within 7 days before treatment start

• Serum albumin ≥ 2.8 g/dL (≥ 28 g/L) within 7 days before treatment start

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 upper limitof normal (ULN)

• Antiviral therapy per local standard of care if active hepatitis B (HBV) infection

• Capable of understanding and complying with the protocol requirements and signedinformed consent

• Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (eg, barrier methods, including male condom, femalecondom, or diaphragm with spermicidal gel) during the course of the study and for 4months after the last dose of study treatment

• Female subjects of childbearing potential must not be pregnant at screening. Femalesof childbearing potential are defined as premenopausal females capable of becomingpregnant (ie, females who have had any evidence of menses in the past 12 months, withthe exception of those who had prior hysterectomy). However, women who have beenamenorrheic for 12 or more months are still considered to be of childbearing potentialif the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovariansuppression, low body weight, or other reasons

Exclusion Criteria:

• Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma

• Child-Pugh score of B or C

• Any type of anticancer agent (including investigational) within 2 weeks beforetreatment start

• Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) orradionuclide treatment (eg, I-131 or Y-90) within 6 weeks of treatment start. Subjectis excluded if there are any clinically relevant ongoing complications from priorradiation therapy

• Prior cabozantinib treatment

• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 3 monthsbefore treatment start. Eligible subjects must be without corticosteroid treatment atthe time of treatment start

• 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).Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dosewarfarin (≤ 1 mg/day), and low-dose LMWH are permitted

• 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 seriouscardiac 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 other ischemic eventwithin 6 months before treatment start.

• iv. Thromboembolic event within 3 months before treatment start. Subjects withthromboses of portal/hepatic vasculature attributed to underlying liver disease and/orliver tumor are eligible

• b. Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation:

• i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory boweldisease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomaticcholangitis or appendicitis, acute pancreatitis or acute obstruction of thepancreatic duct or common bile duct, or gastric outlet obstruction

• ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscesswithin 6 months before treatment start

• Note: Complete healing of an intra-abdominal abscess must be confirmed prior totreatment start

• c. Major surgery within 2 months before treatment start. Complete healing from majorsurgery must have occurred 1 month before treatment start. Complete healing from minorsurgery (eg, simple excision, tooth extraction) must have occurred at least 7 daysbefore treatment start. Subjects with clinically relevant complications from priorsurgery are not eligible

• d. Cavitating pulmonary lesion(s) or endobronchial disease

• e. Lesion invading a major blood vessel including, but not limited to: inferior venacava, pulmonary artery, or aorta. Subjects with lesions invading the portalvasculature are eligible

• f. Clinically significant bleeding risk including the following within 3 months oftreatment start: 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

• g. Other clinically significant disorders such as:

• i. Active infection requiring systemic treatment, known infection with humanimmunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS)-related illness. Subjects with active hepatitis virus infection controlledwith 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

• vii. Rare hereditary problems of galactose intolerance, the Lapp lactasedeficiency or glucose-galactose malabsorption

• Subjects with untreated or incompletely treated varices with bleeding or high risk forbleeding. Subjects treated with adequate endoscopic therapy (according toinstitutional standards)