| Eligibility |
Inclusion Criteria:
1. Hepatocellular Carcinoma (HCC) diagnosed according to criteria of American Association
for the Study of Liver Diseases (AASLD) definition in 2010.
2. Intolerant to sorafenib according to RESORCE trial definition or patients who received
treatment different to sorafenib as first-Line treatment.
3. The subject has disease that is not amenable to a curative treatment approach (eg,
transplant, surgery, radiofrequency ablation)
4. Recovery to = Grade 1 according to (CTCAE) v.5.0. from toxicities related to any prior
treatments, unless the adverse events are clinically non-significant and/or stable on
supportive therapy
5. Respect the 15 days of first-line treatment washout before starting cabozantinib
6. Age = 18 years old on the day of consent
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
8. Adequate hematologic function, based upon meeting the following laboratory criteria
within 7 days before starting therapy:
1. absolute neutrophil count (ANC) = 1200/mm3 (= 1.2 x 10*9/L)
2. platelets = 60,000/mm3 (= 60 x 10*9/L)
3. hemoglobin = 8 g/dL (= 80 g/L)
9. Adequate renal function, based upon meeting the following laboratory criteria within 7
days before starting therapy:
1. Serum creatinine = 1.5 × upper limit of normal or calculated creatinine clearance
= 40 mL/min (using the Cockcroft-Gault equation) AND
2. Urine protein/creatinine ratio (UPCR) = 1 mg/mg (= 113.1 mg/mmol) or 24-hour
urine protein < 1 g
10. Child-Pugh Score of A
11. Total bilirubin = 2 mg/dL (= 34.2 µmol/L) within 7 days before starting therapy
12. Serum albumin = 2.8 g/dL (=28 g/L) within 7 days before starting therapy
13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 5.0 upper limit
of normal (ULN) within 7 days before starting therapy
14. Hemoglobin A1c (HbA1c) = 8% within 28 days before starting therapy (if HbA1c results
are unavailable [eg, hemoglobin variant], a fasting serum glucose = 160 mg/dL)
15. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection
16. Capable of understanding and complying with the protocol requirements and signed
informed consent
17. Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (eg, barrier methods, including male condom, female
condom, or diaphragm with spermicidal gel) during the course of the study and for 4
months after the last dose of study treatment
18. Female subjects of childbearing potential must not be pregnant at screening.
19. Subjects must consent to perform a tumor liver biopsy within 4 weeks before starting
cabozantinib, allowing the acquisition of a tumor sample for performance of
correlative studies.
Exclusion Criteria:
1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
2. Radiation therapy (eg, I-131 or Y-90) within 4 weeks (2 weeks for radiation for bone
metastases or radionuclide treatment within 6 weeks of starting therapy) (subject is
excluded if there are any clinically relevant ongoing complications from prior
radiation therapy)
3. Prior cabozantinib treatment
4. 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 starting therapy. Eligible subjects must be without corticosteroid treatment at
the time of starting therapy.
5. 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.
6. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions
a. Cardiovascular disorders including:
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac
arrhythmias ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg
systolic, or 100 mm Hg diastolic despite optimal antihypertensive treatment iii.
Stroke (including TIA), myocardial infarction, or another ischemic event within 6
months before starting therapy iv. Thromboembolic event within 3 months before
starting therapy. Subjects with thromboses of portal/hepatic vasculature attributed to
underlying liver disease and/or liver tumor are eligible
b. Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel
disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis
or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or
common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation,
bowel obstruction, intra-abdominal abscess within 6 months before starting therapy
iii. Note: Complete healing of an intra-abdominal abscess must be confirmed prior to
starting therapy
c. Major surgery within 2 months before starting therapy. Complete healing from major
surgery must have occurred 1 month before starting therapy. Complete healing from
minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7
days before starting therapy. Subjects with clinically relevant complications from
prior surgery are not eligible
d. Cavitating pulmonary lesion(s) or endobronchial disease
e. Lesion invading a major blood vessel including, but not limited to: pulmonary
artery, or aorta. Subjects with lesions invading the portal vasculature are eligible.
f. Clinically significant bleeding risk including the following within 3 months of
starting therapy: 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
g. Other clinically significant disorders such as:
i. Active infection requiring systemic treatment, known infection with human
immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome
(AIDS)-related illness. Subjects with active hepatitis virus infection controlled with
antiviral therapy are eligible.
ii. Serious non-healing wound/ulcer/bone fracture iii. Malabsorption syndrome iv.
Uncompensated/symptomatic hypothyroidism v. Requirement for hemodialysis or peritoneal
dialysis vi. History of solid organ transplantation
7. Subjects with untreated or incompletely treated varices with bleeding or high risk for
bleeding. Subjects treated with adequate endoscopic therapy (according to
institutional standards) without any episodes of recurrent GI bleeding requiring
transfusion or hospitalization for at least 6 months prior to study entry are
eligible.
8. Moderate or severe ascites. Note that controlled ascites with stable dose of diuretics
in the last month is allowed.
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 7
days before starting therapy
10. Inability to swallow tablets
11. Previously identified allergy or hypersensitivity to components of the study treatment
formulations
12. Pregnant or lactating females
13. Diagnosis of another malignancy within 2 years before starting therapy, except for
superficial skin cancers, or localized, low-grade tumors deemed cured and not treated
with systemic therapy
14. History of allergy to study drug components.
15. Prisoners or subjects who are involuntarily incarcerated
16. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg. infectious disease) illness
17. Inability to comply with restrictions and prohibited activities/treatments.
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