A Phase 2, Single Arm Study of Cabozantinib in Patients With Hepatocellular Carcinoma Who Have Received Prior Atezolizumab and Bevacizumab

Exclusion Criteria

• •• Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
• •Receipt of more than one prior systemic therapy for advanced HCC. Additional prior systemic therapies used as adjuvant or local therapy are allowed.
• •Any type of anticancer agent (including investigational) within 2 weeks before enrollment
• •Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) or radionuclide treatment (eg, I-131 or Y-90) within 6 weeks of enrollment. Subject is excluded if there are any clinically relevant ongoing complications from prior radiation therapy.
• •Prior cabozantinib treatment
• •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 enrollment. Eligible subjects must be without corticosteroid treatment at the time of enrollment.
• •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.
• •The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• •* Cardiovascular disorders including
• •* Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias
• •Uncontrolled hypertension defined as sustained BP \> 150 mm Hg systolic, or \> 100 mm Hg diastolic despite optimal antihypertensive treatment
• •Stroke (including TIA), myocardial infarction, or other ischemic event within 6 months before enrollment
• •Thromboembolic event within 3 months before enrollment. Subjects with thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumor are eligible
• •o Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
• •Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
• •Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before enrollment, Note: Complete healing of an intra-abdominal abscess must be confirmed prior to enrollment
• •* Cavitating pulmonary lesion(s) or endobronchial disease
• •* Lesion invading a major blood vessel (eg, pulmonary artery or aorta)
• •* Clinically significant bleeding risk including the following within 3 months of enrollment: 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
• •* Other clinically significant disorders such as:
• •Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)-related illness
• •Serious non-healing wound/ulcer/bone fracture
• •Malabsorption syndrome
• •Uncompensated/symptomatic hypothyroidism
• •Requirement for hemodialysis or peritoneal dialysis
• •History of solid organ transplantation
• •9\. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding are excluded with the following clarification: subjects with history of prior variceal bleeding must have been treated with adequate endoscopic therapy without any evidence of recurrent bleeding for at least 6 months prior to study entry and must be stable on optimal medical management (e.g. non-selective beta blocker, proton pump inhibitor) at study entry.
• •Moderate or severe ascites
• •Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms within 7 days before enrollment
• •Note: If the QTcF is \> 500 ms in first ECG, a total of 3 ECGs should be performed. If the average of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard.
• •Inability to swallow tablets
• •Previously identified allergy or hypersensitivity to components of the study treatment formulations
• •Pregnant or lactating females
• •Diagnosis of another malignancy within 2 years before enrollment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy