Cabozantinib Combined With Ipilimumab/Nivolumab and TACE in Patients With Hepatocellular Carcinoma

Inclusion Criteria: * Histologic or radiographic diagnosis of hepatocellular carcinoma * At least one lesion amenable to TACE treatment * Child-Pugh A-B7 (B7 based on Albumin allowed) * Not a candidate for resection or transplantation * Age ≥ 18 years. * Performance status: ECOG performance status ≤2 * Must have at least one measurable lesion (either untreated or progressed after previous locoregional treatment) * Adequate organ and marrow function as defined below: 1. Leukocytes ≥ 2,000/mcL 2. absolute neutrophil count ≥ 1000/mcL 3. platelets ≥ 60,000/mcl 4. total bilirubin within normal institutional limits 5. AST(SGOT)/ALT(SPGT) ≤ 3 X institutional upper limit of normal or ≤ 5 X if liver metastases are present 6. creatinine \<1.5ULN 7. hemoglobin ≥ 8 g/dL 8. Serum albumin ≥ 2.8 g/dL 9. Urine protein/creatinine ration (UPCR) ≤ 1 mg/mg * The effects of cabozantinib on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Based on its mechanism of action, ipilimumab can cause fetal harm when administered to a pregnant woman. Females of reproductive potential must use effective contraception during treatment with ipilimumab and for 3 months following the last dose of ipilimumab. Based on its mechanism of action, nivolumab can cause fetal harm when administered to a pregnant woman. Females of reproductive potential must use effective contraception during treatment with nivolumab and for 5 months following the last dose of nivolumab. 1\. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: 1. Has not undergone a hysterectomy or bilateral oophorectomy; or 2. Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). * Life expectancy of greater than 3 months * Ability to swallow tablets * Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria: * Any type of previous systemic anti-cancer treatment * All toxicities attributed to prior anti-cancer therapy other than alopecia must have resolved to grade 1 or baseline * Any locoregional treatment for HCC within 3 months * Vp4 or Vp3 portal vein thrombus * Extrahepatic disease * Patients may not be receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab, cabozantinib or other agents used in study. * Concomitant anticoagulation with coumarin agents (eg, warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitors (e.g., rivaroxaban), or platelet inhibitors (eg, clopidogrel). Allowed anticoagulants are the following: 1. Prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines) and low dose low molecular weight heparins (LMWH). 2. Therapeutic doses of LMWH in subjects with a screening platelet count \> 100,000/μL, without known brain metastases, and who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor. * The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 28 days before the first dose of study treatment. * Uncontrolled intercurrent illness including, but not limited to, the following conditions: 1. ongoing or active infection 2. symptomatic congestive heart failure 3. uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment 4. Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 6 months before first dose 5. unstable angina pectoris 6. cardiac arrhythmia 7. evidence of tumor invading GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, 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. 8. 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. 9. Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose. 10. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. 11. Lesions invading any major blood vessels. Subjects with lesions invading the intrahepatic vasculature, including portal vein, hepatic vein, and hepatic artery, are eligible. 12. Other clinically significant disorders that would preclude safe study participation: 1. Serious non-healing wound/ulcer/bone fracture 2. Uncompensated/symptomatic hypothyroidism 3. Moderate to severe hepatic impairment (Child-Pugh B or C) 13. psychiatric illness/social situations that would limit compliance with study requirements. * Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis) within