The purpose of this study is to evaluate Sorafenib and local microtherapy guided by Primovist enhanced MRI in patients with inoperable liver cancer (HCC).

Methodology:

Patients with a diagnosis of hepatocellular carcinoma will receive either:

• local ablation therapy of liver lesions by radiofrequency ablation followed by sorafenib or placebo (local ablation group), or
• radioembolization (SIRT) + sorafenib or sorafenib alone (palliative treatment group).

In each study group, patients will be randomized to one of the two treatment arms following a pre-defined randomization plan. Randomization will be on a 1:1 basis in the local ablation group and on the basis of 10 (sorafenib only) : 11 (SIRT + sorafenib) in the palliative treatment group.

Patients in the local ablation group will be followed at 2 months intervals for recurrence and overall survival, patients in the palliative treatment group will be followed for overall survival. Follow-up in each study group will end 24 months after inclusion of the last patient into the respective study group.

The assignment of patients to the local ablation or palliative study group will be based on the ablative potential of RFA (local ablation if ≤4 tumors, each ≤5 cm in size). Diagnostic imaging will be used to guide this decision. The assignment to the local ablation or the palliative treatment group will be made by the local investigator.

As a sub-study, all patients will undergo Primovist®-enhanced MRI in addition to contrast-enhanced CT before assignment to one treatment group. The goal of the sub-study is to assess the value of Primovist®-enhanced MRI to correctly stratify patients for a local ablation or palliative treatment strategy. Primovist®-enhanced MRI will be compared with contrast-enhanced multislice CT using a truth panel assessment as the standard of reference. In addition, Primovist-enhanced MRI and contrast-enhanced CT will be obtained during follow-up of patients in the local ablation group to assess its potential for detection of recurrence.

Inclusion Criteria

1. Age: 18-85 years

2. Diagnosis of hepatocellular carcinoma

3. If primary diagnosis of HCC: diagnosis based on the following criteria:

   1. cyto-histological criteria, OR
   2. radiological criteria: Focal lesion >1 cm with arterial hypervascularization in 2 coincident imaging techniques (CT, MRI, or US), OR
   3. combined criteria: one imaging technique showing a focal lesion 1-2 cm with arterial hypervascularization AND AFP levels >400 ng/mL, OR
   4. combined criteria: one imaging technique showing a focal lesion >2 cm with arterial hypervascularization AND AFP levels >200 ng/mL

4. If extrahepatic metastases: liver-dominant disease

5. Stage BCLC A, B, or C

6. Child-Pugh A, Child-Pugh B up to 7 points (in patients receiving anticoagulant therapy: Child-Pugh score up to 5 points; INR category not regarded for calculation of the Child-Pugh score)

7. Willing to comply with all study procedures

8. Has voluntarily given written informed consent

Exclusion Criteria

1. If female, pregnant or breast feeding (females of child-bearing potential must use adequate contraception and must have a negative pregnancy test performed within 7 days prior to inclusion into this study)

2. If male, not using adequate birth control measures

3. One or more of the following:

   • Hemoglobin <10g/dL,
   • WBC <2,500 cells/mm3,
   • ANC <1,500 cells/mm3,
   • platelets <50,000/mm3,
   • ECOG performance status >2

4. Life expectancy <16 weeks or medically unstable

5. Extrahepatic metastases (except metastases to bone, lymph nodes, and adrenal glands which do not constitute an exclusion criterion), but, see Additional Criteria for the Local Ablation Group, below (Section 4.2 of the study protocol)

6. Patients with known GFR <30 mL/min/1.73m2

7. PT-INR/PTT >1.5 times the upper limit of normal (patients on anticoagulation therapy will be allowed to participate provided that no prior evidence exists of an underlying abnormality in anticoagulation)

8. Uncontrolled infections at the time of microtherapy

9. Child-Pugh score >7 points; in patients receiving anticoagulant therapy: Child-Pugh score >5 points (INR category not regarded for calculation of the Child-Pugh score)

10. Uncontrolled ascites

11. Tumor load of the whole liver >70%

12. Contraindications for study medications according to product labeling or procedures (sorafenib, Primovist®, x-ray contrast agents, SIR-Spheres®, RFA, MWA, MRI, CT) incl. any contraindication to the transarterial interventional procedure (e.g., allergy against x-ray contrast agents, uncontrolled hyperthyroidism)

13. Prior resection of the papilla of Vater (e.g., Whipple procedure) or bile duct stent across the papilla

14. Significant cardiovascular disease; e.g., myocardial infarction within 6 months of inclusion, chronic heart failure (New York Heart Association class III or IV), unstable coronary artery disease

15. Uncontrolled hypertension

16. Thrombotic or embolic events including transient ischemic attacks within the past 6 months (tumor-related portal vein thrombosis allowed in the palliative part of the trial).

17. History of GI bleeding within 30 days before inclusion into this study

18. History of esophageal varices bleeding which has not been controlled by effective therapy and/or therapy to prevent bleeding recurrence

19. Previous malignancy other than carcinoma in situ of the skin or the cervix uteri within 5 years prior to inclusion

20. History of organ transplant (including prior liver transplantation)

21. HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease (rheumatoid arthritis) or inflammatory bowel disease

22. Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial

23. Close affiliation with the investigational site; e.g. first-degree relative of the investigator

24. Participating in another therapeutic clinical trial or has completed study participation in another therapeutic clinical trial within 30 days of enrolment into this trial

25. Having been previously enrolled in this clinical trial