Cabozantinib for Patients with Hepatocellular Carcinoma (HCC) Refractory to First Line Treatment

Inclusion Criteria:

1. Fully-informed written consent.

2. Males and females ≥ 18 years of age.

*There are no data that indicate special gender distribution. Therefore, patientswill be enrolled in the study gender-independently.

3. Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed byhistology/ cytology or clinically by guideline criteria in cirrhotic patients

4. Disease that is not amenable to curative surgical and/or locoregional therapies, orprogressive disease after surgical and /or locoregional therapies.

5. Patients who have shown progressive disease during or after first line therapy ORpatients must have had their treatment interrupted due to the level of toxicitiesAND cabozantinib therapy is intended as second line therapy.

6. ECOG performance status ≤ 2.

7. Resolution of any acute, clinically significant treatment-related toxicity fromprior therapy to Grade 1 prior to study entry, with the exception of alopecia.

8. For women of childbearing potential and men who are sexually active with women ofchildbearing potential: agreement to remain abstinent (refrain from heterosexualintercourse) or use contraceptive methods.

Exclusion Criteria:

1. Unwillingness to give informed consent for participation in the study.

2. Prior sorafenib treatment.

3. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatmentor within at least 5 months after last dose of study treatment.

4. Women of childbearing potential must have a negative serum pregnancy test resultwithin 14 days prior to initiation of study treatment.

5. Significant portal hypertension (moderate or severe ascites).

6. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

7. Liver cirrhosis Child-Pugh B with > 7 points and Child-Pugh C.

8. Severely impaired kidney function.

9. History of encephalopathy in past 12 months, if not completely regressive or morethan one episode within the last 6 months.

10. Significant cardiovascular disease (such as New York Heart Association Class II orgreater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstableangina.

11. Baseline QTcF >500 ms.

12. Major surgical procedure, other than for diagnosis, within 4 weeks prior toinitiation of study treatment, or anticipation of need for a major surgicalprocedure during the study.

13. Severe infection within 4 weeks prior to initiation of study treatment, including,but not limited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia.

14. Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications.

15. Elevations of AST/ALT exceeding 5 X ULN.

16. Treatment with investigational systemic therapy within 28 days prior to initiationof study treatment.

17. Prior cabozantinib use.

18. Is currently participating or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study treatment.

19. Patients who have been incarcerated or involuntarily institutionalized by courtorder or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.

20. Patients who are unable to consent because they do not understand the nature,significance and implications of the clinical trial and therefore cannot form arational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].