Overview

This is a phase 2 single-arm, open-label clinical trial determining efficacy of cabozantinib in combination with ipilimumab/nivolumab and transarterial chemoembolization (TACE) in subjects with hepatocellular carcinoma (HCC). These are subjects who are not candidates for curative intent treatment.

Eligibility

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 2 weeks before first dose of study treatment. Minor surgeries
             within 10 days before first dose. Subjects must have complete wound healing from major
             surgery or minor surgery before first dose of study treatment. Subjects with
             clinically relevant ongoing complications from prior surgery are not eligible.
          -  Prior treatment with cabozantinib
          -  Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
             electrocardiogram (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 investigational
             kinase inhibitor) within 2 weeks before first dose of study treatment.
          -  History of another primary cancer within the last 3 years with the exception of
             non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical
             carcinoma in-situ and not treated with systemic therapy.
          -  Inability to comply with study and follow-up procedures as judged by the Investigator
          -  Patients must not be pregnant or nursing due to the potential for congenital
             abnormalities and the potential of this regimen to harm nursing infants
          -  Has fibrolamellar HCC
          -  Has received prior cytotoxic, biologic or other systemic anticancer therapy including
             investigational agents within 4 weeks prior to randomization.
          -  Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy
             within 4 weeks before first dose of study treatment. Systemic treatment with
             radionuclides within 6 weeks before the first dose of study treatment. Subjects with
             clinically relevant ongoing complications from prior radiation therapy are not
             eligible.
          -  Has received a live vaccine within 30 days prior to the first dose of study
             intervention. Examples of live vaccines include, but are not limited to, the
             following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever,
             rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza
             vaccines for injection are generally killed virus vaccines and are allowed; however,
             intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not
             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 of
             immunosuppressive therapy within 7 days prior to the first dose of study intervention.
          -  Has severe hypersensitivity (Grade ≥ 3) to nivolumab or cabozantinib and/or any of
             their excipients.
          -  Has an active autoimmune disease that has required systemic treatment in past 2 years
             (i.e., with use of disease-modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency) is not considered a form
             of systemic treatment and is allowed.
          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.
          -  Has an active infection requiring systemic therapy.
          -  Has a known history of human immunodeficiency virus (HIV) infection. Note: No HIV
             testing 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 the enzyme
             dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality that might
             confound the results of the study, interfere with the participant's participation for
             the full duration of the study, or is not in the best interest of the participant to
             participate, in the opinion of the treating investigator.