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

Prior treatment

• 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
• Severe infection with alteration of general condition within four weeks prior to initiation of study treatment
• Myocardial infarction within 12 months prior to initiation of study treatment
• Prior Cabozantinib use
• 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
• Participation in any other interventional trials within 28 days prior to initiation of study treatment
• Suspected lack of compliance to previous treatments; inability to take the medication

Other illness

• Significant portal hypertension (moderate or severe ascites)
• No adequate controlled arterial hypertension (RR \> 140/80mmHg)
• Epilepsy
• 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)
• Chronic inflammatory bowel disease (e.g. colitis ulcerosa, diverticulitis, Crohn's disease)
• Increased risk of thromboembolism due to medical history or disease
• Known active HIV infection
• 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

Lab values

• Severely impaired kidney function (CDK: stadium 4: GFR\<30)
• Heart failure, Cardiac arrhythmia, respectively long-QT syndrome
• Known hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption
• Ongoing therapy with direct oral anticoagulants (DOAK) / platelet aggregation inhibitor or statine (e.g. Ticagrelor, Clopidogrel)

Other

• ALAT/ASAT five times higher then upper normal value
• Hepatic encephalopathy (every stage)
• Liver cirrhosis Child-Pugh B and C
• Known fibrolamellar HCC, sarcomatoid HCC, or cholangiocarcinoma mixed with HCC
• Significant alcohol consumption (\>1 drink/day; 1 drink=0.25l beer or 0,1l wine or 2cl spirituous beverages)
• Predicted life expectancy of less than 6 months
• Pregnancy or lactation, or intention of becoming pregnant during study treatment

• Patients with diagnosis of locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC)
• 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)
• Disease progression or end of therapy due to toxicity during/after pre-therapy
• CTCAE ≤ Grade 2 prior to study registration, with the exception of alopecia
• ECOG (Eastern Cooperative of Onco-logy Group) Index 0 or 1
• Age ≥ 18 years
• Written informed consent