Cabozantinib Treatment in a Phase II Study for Patients With Hepatocellular Carcinoma (HCC) Refractory to PD-1 Inhibitors

The CaPture trial is a prospective, multi-centre, non-randomized phase II study. Its aim is to assess feasibility, safety and efficacy signals of Cabozantinib treatment in patients with HCC and prior non-response or disease progression during a PD-1 or PD-L1 inhibitor treatment. Since the potential study population is very small, the sample size has been fixed in advance to N = 40. Time on treatment (TT) will be measured as primary endpoint.

Patients will be recruited at the participating trial sites (up to ten trial sites), which are all specialized in treatment of patients with HCC. Once potential patients are identified by trial physicians, they will be asked for trial participation and informed consent by one investigator of the CaPture trial. Patients included within 4 weeks after diagnosis of failure of preceding PD-1/PD-L1 inhibitory treatment.

After baseline, visits are previewed on a 4weekly (28 days) basis during the whole duration of Cabozantinib study treatment, which can be used for a maximum of 12 months (336 days). The treatment with Cabozantinib will be performed in accordance with the valid license and according to the judgement of the treating physician.The tablet is taken once a day, starting normally with the highest dosage (60 mg). The doses 20mg and 40mg are still available and can be used for dose reduction. During the visits, the patient will be questioned for compliance and side effects and examined for clinical and laboratory parameters.

Response to Cabozantinib should be assessed at least every 12 weeks (84 days) by either CT scan or MRI.

After termination of Cabozantinib study treatment the first follow-up visit takes place one month after the end of therapy in person. Further follow-up visits can be done by phone to collect patient's status and further treatment.

In addition to the time on treatment (TT), survival, response, feasibility, biomarkers, health status and safety should also be tested.

Furthermore there is an concomitant scientific project. The aim of this project is to examinate the association of HCC related biomarkers with response to Cabozantinib in patients treated in the CaPture study. For this, we will analyse liver biopsy samples as well as circulating markers in patients who are willing to participate in the project.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with diagnosis of locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC)
2. Pre-Treatment with a PD-1/PD-L1 inhibitor for at least one administration which was given as first line or as following line systemic treatment alone or in combination with other systemic or local treatments (e.g. TACE)
3. Disease progression or end of therapy due to toxicity during/after pre-therapy
4. CTCAE ≤ Grade 2 prior to study registration, with the exception of alopecia
5. ECOG (Eastern Cooperative of Onco-logy Group) Index 0 or 1
6. Age ≥ 18 years
7. Written informed consent

Exclusion Criteria:

1. Significant portal hypertension (moderate or severe ascites)
2. No adequate controlled arterial hypertension (RR \> 140/80mmHg)
3. ALAT/ASAT five times higher then upper normal value
4. Hepatic encephalopathy (every stage)
5. Liver cirrhosis Child-Pugh B and C
6. Known fibrolamellar HCC, sarcomatoid HCC, or cholangiocarcinoma mixed with HCC
7. Major surgical procedure, other than for diagnosis, within eight weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
8. Severe infection with alteration of general condition within four weeks prior to initiation of study treatment
9. Severely impaired kidney function (CDK: stadium 4: GFR\<30)
10. Myocardial infarction within 12 months prior to initiation of study treatment
11. Epilepsy
12. Heart failure, Cardiac arrhythmia, respectively long-QT syndrome
13. Severe bleeding or high risk for the development of severe bleeding, including esophageal varices \> 1° or esophageal varices with red marks as seen on a lighted stomach scope (endoscopy)
14. Chronic inflammatory bowel disease (e.g. colitis ulcerosa, diverticulitis, Crohn's disease)
15. Increased risk of thromboembolism due to medical history or disease
16. Significant alcohol consumption (\>1 drink/day; 1 drink=0.25l beer or 0,1l wine or 2cl spirituous beverages)
17. Known active HIV infection
18. Known hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption
19. Prior Cabozantinib use
20. Ongoing therapy with direct oral anticoagulants (DOAK) / platelet aggregation inhibitor or statine (e.g. Ticagrelor, Clopidogrel)
21. Predicted life expectancy of less than 6 months
22. Female patients who do not meet at least one of the following criteria:

    * Postmenopausal women (for at least 1 year before the screening visit) OR
    * Postoperative status (6 weeks after bilateral ovariectomy with or without hysterectomy) OR
    * If they are of childbearing potential, agree to practice one highly effective method of contraception and one additional effective (barrier) method at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR
    * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) OR
    * Abstinence OR
    * Vasectomy of the partner
23. Male patients not using one of the following variants for contraception including a period of 4 months after the completion of the therapy:

    * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. OR
    * Condition after vasectomy OR
    * Condom
24. Participation in any other interventional trials within 28 days prior to initiation of study treatment
25. Suspected lack of compliance to previous treatments; inability to take the medication
26. Pregnancy or lactation, or intention of becoming pregnant during study treatment