Cabozantinib for the Treatment of Liver Cancer with Child Pugh Class B Cirrhosis after First-Line Therapy

Inclusion Criteria

• Patients must have a radiologically consistent (early enhancement and delayed enhancement washout) or pathologically confirmed diagnosis of hepatocellular carcinoma that is not eligible for curative resection, transplantation, or ablative therapies
• Prior radiation, liver directed therapy (including bland, chemo- or radioembolization, or ablation), or hepatic resection are permitted if >= 4 weeks from start of therapy. Extra-hepatic palliative radiation is permitted if completed >= 2 weeks prior to first dose of study therapy and the patient has recovered to =< grade 1 toxicity
• Patients must have radiographically measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) in at least one site not previously treated or with progression after radiation or liver directed therapy (including bland, chemo- or radio-embolization, or ablation) either within the liver or in a metastatic site
• Patients must have either progressed or deemed intolerant of first-line systemic therapy. More than one line of systemic therapy is not permitted. The last dose should be at least 2 weeks from first dose of study therapy. Prior treatment may not contain cabozantinib
• Recovery to =< grade 1 from toxicities related to any prior treatments, unless the adverse events (AEs) were clinically non-significant and/or stable on supportive therapy
• Must be >= 18 years of age
• Must have a Child-Pugh score of B7 or B8
• Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent
• Willing to provide archived tissue, if available, from a previous diagnostic biopsy
• Must be able to tolerate computed tomography (CT) and/or magnetic resonance imaging (MRI) with contrast
• Absolute neutrophil count >= 1200/mm^3 (obtained =< 2 weeks prior to enrollment)
• Hemoglobin >= 8.5 g/dL (obtained =< 2 weeks prior to enrollment)
• Platelets >= 60,000/mm^3 (obtained =< 2 weeks prior to enrollment)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) (obtained =< 2 weeks prior to enrollment)
• Creatinine clearance >= 40 mL/min (obtained =< 2 weeks prior to enrollment)
• Albumin >= 2.8 g/dL (obtained =< 2 weeks prior to enrollment)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5.0 x ULN (obtained =< 2 weeks prior to enrollment)
• Total bilirubin =< 3.0 mg/dL (obtained =< 2 weeks prior to enrollment)
• International Normalized Ratio (INR) =< 2.3 (obtained =< 2 weeks prior to enrollment)
• No known brain metastasis unless adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks before registration. Eligible subjects must have been without corticosteroid treatment at the time of registration
• Women of child-bearing potential (not surgically sterilized and between menarche and 1-year post menopause) and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 4 months following completion of study therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Concomitant treatment with strong inducers or inhibitors of CYP3A4 is not allowed. Patients must discontinue the drug(s) at least 14 days prior to first study dose on the study
• Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin and factor Xa inhibitors), or platelet inhibitors (e.g. clopidogrel) is not allowed. The following anticoagulants are allowed: * Low dose aspirin * Prophylactic dose low molecular weight heparin * Therapeutic dose low molecular weight heparin is allowed in subjects without brain metastasis who have been on a stable dose for at least 6 weeks before the first dose of study therapy, and have had no clinically significant hemorrhagic complications from the anticoagulation regimen

Exclusion Criteria

• Must not have uncontrolled ascites (requiring paracentesis within 3 months of screening) or hepatic encephalopathy requiring hospitalization (within 6 months of screening)
• Must not have prior history of organ transplantation
• Must not have undergone a major surgery (e.g., gastrointestinal [GI] surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
• Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ. Patients with history of malignancy are eligible provided primary treatment of that cancer was completed > 1 year prior to enrollment and the patient is free of clinical or radiologic evidence of recurrent or progressive malignancy
• Must not have uncontrolled, significant intercurrent or recent illness including, but not limited to the following conditions: *. Cardiovascular disorders: ** Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias. ** Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment ** Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: ** The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ** Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose * Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose * Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation * Lesions invading or encasing any major blood vessels except thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumor * Other clinically significant disorders that would preclude safe study participation ** Serious non-healing wound/ulcer/bone fracture ** Uncompensated/symptomatic hypothyroidism ** Known human immunodeficiency virus (HIV)
• Must not have untreated or incompletely treated varices with bleeding or high risk for bleeding. Subjects treated with adequate endoscopic therapy (in accordance with institutional standards) without any episodes of recurrent overt GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible
• Must not have a psychiatric illness, other significant medical illness, or social situation (such as involuntary incarceration) which, in the investigator’s opinion, would limit compliance or ability to comply with study requirements
• Women must not be pregnant or breastfeeding since cabozantinib may harm the fetus or child. All females of childbearing potential (not surgically sterilized and between menarche and 1-year post menopause) must have a blood or urine test to rule out pregnancy within 2 weeks prior to registration
• Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness would be excluded
• Must not have corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days before first dose of study treatment. Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility