TACE With or Without Sorafenib in Intermediate Stage Hepatocellular Carcinoma

Transarterial Chemoembolization (TACE) With or Without Sorafenib in Intermediate Stage Hepatocellular Carcinoma: a Multicenter Prospective Nonrandomized Study

This multicenter prospective nonrandomized study is to evaluate the efficacy of TACE combined with sorafenib compared with TACE monotherapy in term of overall survival in intermediate-stage HCC.

Sorafenib, a multikinase inhibitor, has been successfully applied for solid tumors such as renal cancer and HCC.

According to the Barcelona Clinic Liver Cancer (BCLC) staging classification, transarterial chemoembolization (TACE) has been recommended as a first line-therapy for patients at intermediate stage - BCLC B class (multinodular asymptomatic tumors without an invasive pattern).

Because sorafenib may improve the efficacy of locoregional therapy by decreasing post-TACE angiogenesis, sorafenib in combination with TACE has attracted considerable attention as a promising therapy

Inclusion Criteria:

1. Prior informed consent

2. Intermediate stage HCC/ BCLC B stage

3. Confirmed Diagnosis of HCC:

   1. Cirrhotic subjects: Clinical diagnosis by AASLD criteria. HCC can be defined in cirrhotic subjects by one imaging technique (CT scan, MRI, or second generation contrast ultrasound) showing a nodule larger than 2 cm with contrast uptake in the arterial phase and washout in venous or late phases or two imaging techniques showing this radiological behavior for nodules of 1-2 cm in diameter. Cytohistological confirmation is required for subjects who do not fulfill these eligibility criteria.
   2. Non-cirrhotic subjects: For subjects without cirrhosis, histological or cytological confirmation is mandatory. Documentation of original biopsy for diagnosis is acceptable

4. Child Pugh class A/B(7) class without ascites or hepatic encephalopathy

5. ECOG Performance Status of 0-1

6. At least one uni-dimensional lesion measurable by CT-scan or MRI according to the RECIST 1.1, mRECIST and EASL criteria, respectively.

   1. Single lesion>5cm
   2. 2-3 lesions, at least one lesion>3cm; if more than 4 lesions, no limitation of the tumor size, but the sum of size of all tumor lesions should be less than 50% of liver parenchyma.

7. Male or female subject ≥ 18 years of age

8. Ability to swallow oral medications

9. Life expectancy of at least 12 weeks

10. Pregnancy test negative within 14 days before treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 4 weeks after the completion of trial

11. Adequate bone marrow, liver and renal functions as assessed by central lab by means of the following laboratory requirements from samples within 7 days prior to randomization:

    1. Hemoglobin > 9.0 g/dl
    2. Absolute neutrophil count (ANC) >1,500/mm3
    3. Platelet count ≥50x109/L
    4. ALB ≥28g/L
    5. Total bilirubin < 2 mg/dL
    6. ALT and AST < 5 x upper limit of normal
    7. BUN and creatinine < 1.5 x upper limit of normal
    8. INR < 1.7, or PT < 4 seconds above control

Exclusion Criteria:

1. Diffuse HCC or tumor size ≥50% of liver parenchyma

2. Vascular invasion

3. Presence of extrahepatic metastasis

4. Poor blood supply for the liver tumor lesions; poor blood supply refers that the tumor lesions fail to show obvious contrast uptake in the arterial phase and washout in venous or late phases by CT scan or MRI

5. Any contraindications for hepatic embolization procedures:

   1. Known hepatofugal blood flow
   2. Known porto-systemic shunt
   3. Renal failure / insufficiency requiring hemo-or peritoneal dialysis

6. Target lesions having previously been treated with local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI)

7. Investigational drugs or other molecular target drugs ongoing or completed < 4 weeks prior to the baseline scan

8. Prior transarterial embolization or anti-tumor systemic chemotherapy

9. Any ≥ CTC AE grade 2 acute toxic effects of any prior local treatment

10. Patients with untreated varices or active bleeding

11. History of cardiac disease:

    1. Congestive heart failure >New York Heart Association (NYHA) class 2
    2. Uncontrolled hypertension

12. Known history of HIV infection

13. Active clinically serious infections (> grade 2 NCI-CTCAE Version 4.0), except for HBV and HCV infection

14. Clinically significant gastrointestinal bleeding within 4 weeks prior to start of study drug

15. Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months prior to the first dose of study drug

16. Previous or concurrent cancer that is distinct in primary site or histology from HCC. Any cancer curatively treated >3 years prior to entry is permitted

17. Any contraindication for sorafenib or doxorubicin administration

18. Pregnant or breast-feeding subjects

19. Any disease which could affect the evaluation of the study drug: unstable angina, active CAD, uncontrolled arrhythmias, and myocardial infarction

20. Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study

21. Major surgery within 4 weeks prior to start of study drug (e.g. thoracolaparotomy is not allowed, but noninvasive surgery, e.g. biopsy, is allowed)

22. Autologous bone marrow transplant or stem cell rescue within 1 year prior to start of study drug

23. History of organ allograft