Dose Escalation Study of Cabozantinib for Advanced HCC Patients With Preserved Liver Function

Prior treatment

• Significant cardiovascular disease (such as NYHA Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study.
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• Treatment with investigational systemic therapy within 28 days or five times the elimination half-life of the investigational product, whichever is longer, prior to initiation of study treatment.
• Prior cabozantinib use.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

Other illness

• Significant portal hypertension (moderate or severe ascites). Significant hypertension, defined as blood pressure ≥ 140 mmHg (systolic) or ≥ 90 mmHg (diastolic) in repeated measurements.
• Known or suspected hypersensitivity to cabozantinib or any other excipients of the IMP.

Lab values

• Severely impaired kidney function (defined as creatinine \> 2 mg/dl and/or creatinine clearance \< 45 mL/min).
• Elevations of AST/ALT \> 5 x ULN at baseline.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
• Rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Other

• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 4 months.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Patients with impaired liver function defined as Child-Pugh B or C, if liver cirrhosis is present.
• Presence of encephalopathy in past 12 months.
• Baseline QTcF \> 500 ms.
• Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
• Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts \[§ 40 Abs. 1 S. 3 Nr. 3a AMG\].

• Fully-informed written consent.
• Males and females ≥ 18 years of age.
  • \*There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
• Patients with HCC who have been previously treated with any first line therapy.
• Locally advanced or metastatic and/or unresectable HCC with preserved liver function (Child-Pugh A only, if liver cirrhosis is present) with diagnosis confirmed by histology/cytology or clinically by guideline criteria.
• Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and/or locoregional therapies.
• ECOG performance status ≤ 2.
• Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade 1 prior to study entry, with the exception of alopecia.
• Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
• For women of childbearing potential (WOCBP): agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods from the time of signing the informed consent through at least 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Male patients, even if surgically sterilized (i.e. status post-vasectomy) must agree to practice effective barrier contraception (e.g. condom) and to refrain from sperm donation during the entire study treatment period and through at least 4 months after the last dose of study drug or agree to completely abstain from heterosexual intercourse.