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

Open-label, single arm, multicenter phase II trial assessing the tolerability of a reduced starting dose of 40 mg cabozantinib for 4 weeks and subsequent dose escalation to 60 mg cabozantinib until disease progression or intolerable toxicities.

The primary objective is to assess the tolerability of a reduced starting dose of 40 mg cabozantinib once-daily for 4 weeks and subsequent dose escalation to 60 mg cabozantinib once-daily to be maintained until disease progression or intolerable toxicities. Using the same study treatment discontinuation criteria as in the pivotal CELESTIAL trial will allow for comparison of treatment discontinuation rates due to treatment related adverse events (TRAEs) defined as unresolved intolerable Grade 2 TRAEs or any unresolved Grade 3 TRAEs (see Section 6).

Patients eligible for this trial are HCC patients with preserved liver function previously treated with any first line therapy.

Secondary objectives comprise the assessment of overall survival (OS), progression free survival (PFS) at 10 weeks, objective response rate (ORR), time on treatment, treatment exposure (dose intensity/dose reductions), toxicity, and quality of life (QLQ-C30).

In addition, tissue samples (optional) will be analyzed for molecular parameters and immune cell composition to identify biomarkers potentially associated with clinical efficacy (OS, PFS and ORR).

This is an open label, single-arm, multicenter phase II trial. 40 patients suffering from advanced stage hepatocellular carcinoma (HCC) with preserved liver function in second line treatment, after any first line therapy, will be enrolled in this trial.

Patients will be recruited from up to 10 sites and patients withdrawn from the trial will not be replaced.

Eligibility Criteria:
Inclusion Criteria:

* 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.

Exclusion Criteria:

* Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 4 months.
* Significant portal hypertension (moderate or severe ascites). Significant hypertension, defined as blood pressure ≥ 140 mmHg (systolic) or ≥ 90 mmHg (diastolic) in repeated measurements.
* 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.
* 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.
* Presence of encephalopathy in past 12 months.
* 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.
* Baseline QTcF \> 500 ms.
* 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.
* 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.
* 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.
* Known or suspected hypersensitivity to cabozantinib or any other excipients of the IMP.
* Rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
* 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.
* 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 \[§ 40 Abs. 1 S. 3 Nr. 3a AMG\].