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 afterprevious 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 livermetastases 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 recommendedtherapeutic dose are unknown. For this reason, women of child-bearing potential andmen must agree to use adequate contraception (hormonal or barrier method of birthcontrol; abstinence) prior to study entry, for the duration of study participation,and for 4 months following completion of therapy. Should a woman become pregnant orsuspect she is pregnant while participating in this study, she should inform hertreating 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 thefollowing criteria:

2. Has not undergone a hysterectomy or bilateral oophorectomy; or

3. Has not been naturally postmenopausal for at least 12 consecutive months (i.e., hashad 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 haveresolved 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 orbiologic composition to nivolumab, cabozantinib or other agents used in study.

• Concomitant anticoagulation with coumarin agents (eg, warfarin), direct thrombininhibitors (e.g., dabigatran), direct factor Xa inhibitors (e.g., rivaroxaban), orplatelet inhibitors (eg, clopidogrel). Allowed anticoagulants are the following:

1. Prophylactic use of low-dose aspirin for cardioprotection (per local applicableguidelines) 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 theanticoagulant for at least 1 week before first dose of study treatment withoutclinically significant hemorrhagic complications from the anticoagulationregimen 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 followingconditions:

1. ongoing or active infection

2. symptomatic congestive heart failure

3. uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hgsystolic 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, inflammatorybowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomaticcholangitis or appendicitis, acute pancreatitis, acute obstruction of thepancreatic duct or common bile duct, or gastric outlet obstruction.

8. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominalabscess within 6 months before first dose.Note: Complete healing of an intra-abdominal abscess must be confirmed beforefirst 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, pulmonaryhemorrhage) within 12 weeks before first dose.

10. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation.

11. Lesions invading any major blood vessels. Subjects with lesions invading theintrahepatic vasculature, including portal vein, hepatic vein, and hepaticartery, are eligible.

12. Other clinically significant disorders that would preclude safe studyparticipation:

13. Serious non-healing wound/ulcer/bone fracture

14. Uncompensated/symptomatic hypothyroidism

15. Moderate to severe hepatic impairment (Child-Pugh B or C)

16. psychiatric illness/social situations that would limit compliance with studyrequirements.

• Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy ofbrain metastasis) within 2 weeks before first dose of study treatment. Minorsurgeries within 10 days before first dose. Subjects must have complete woundhealing from major surgery or minor surgery before first dose of study treatment.Subjects with clinically relevant ongoing complications from prior surgery are noteligible.

• Prior treatment with cabozantinib

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 28 days before first dose of study treatment.

Corrected QT (QTc) = QT / ∛RR

QT: duration of QT interval RR: duration of RR interval

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.

• Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks before first dose of study treatment.

• History of another primary cancer within the last 3 years with the exception ofnon-melanoma skin cancer, early-stage prostate cancer, or curatively treatedcervical carcinoma in-situ and not treated with systemic therapy.

• Inability to comply with study and follow-up procedures as judged by theInvestigator

• Patients must not be pregnant or nursing due to the potential for congenitalabnormalities and the potential of this regimen to harm nursing infants

• Has fibrolamellar HCC

• Has received prior cytotoxic, biologic or other systemic anticancer therapyincluding investigational agents within 4 weeks prior to randomization.

• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before the first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible.

• Has received a live vaccine within 30 days prior to the first dose of studyintervention. Examples of live vaccines include, but are not limited to, thefollowing: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever,rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenzavaccines for injection are generally killed virus vaccines and are allowed; however,intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and arenot allowed.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of studyintervention.

• Has severe hypersensitivity (Grade ≥ 3) to nivolumab or cabozantinib and/or any oftheir excipients.

• Has an active autoimmune disease that has required systemic treatment in past 2years (i.e., with use of disease-modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered a form of systemic treatment and is allowed.

• Has a history of (non-infectious) pneumonitis that required steroids or has currentpneumonitis.

• Has an active infection requiring systemic therapy.

• Has a known history of human immunodeficiency virus (HIV) infection. Note: No HIVtesting is required unless mandated by local health authority.

• Has a known history of active tuberculosis (TB; Bacillus tuberculosis).

• Has a history or current evidence of any condition (eg, known deficiency of theenzyme dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality thatmight confound the results of the study, interfere with the participant'sparticipation for the full duration of the study, or is not in the best interest ofthe participant to participate, in the opinion of the treating investigator.