Sorafenib Chemoembolization Evaluation Controlled Trial

This prospective, multicenter, randomized, controlled study aims to evaluate the efficacy and safety of sorafenib combined with transarterial chemoembolization (TACE) in advanced hepatocellular carcinoma (HCC) patients compared with sorafenib alone, and to determine the prognostic factors that influence the survival.

Data on the efficacy and safety of sorafenib in combination with TACE in patients with advanced HCC are lacking. Because in western countries, advanced HCC is considered as a contraindication for TACE treatment. However, clinical practice patterns differ markedly between Asia and western countries: in Asia TACE is performed in selected advanced HCC patients. We consider sorafenib combined with TACE could achieve better survival benefit than sorafenib alone in selected advanced HCC patients.

PRIMARY OBJECTIVE:

To compare the overall survival of selected advanced HCC patients treated with sorafenib combined with TACE with sorafenib alone.

SECONDARY OBJECTIVES:

1. To compare the time to progression (TTP, according to mRECIST criteria).
2. To compare the tumor response and disease control rate according to Response Evaluation Criteria in Solid Tumors (RECIST1.1), modified Response Evaluation Criteria in Solid Tumors (mRECIST) and European Association of Liver Disease (EASL) criteria.
3. To compare the safety.

OTHER OBJECTIVES:

1. To explore the prognostic value of AFP response after treatment.

OUTLINE: This is a multicenter, phase 3, prospective, randomized, controlled trial. Patients are stratified according to

1. ECOG ( 0 vs. 1)
2. Tumor burden

   1. single vs. multiple lesions
   2. tumor size (\>8cm vs. ≤8cm)
   3. vascular invasion (yes vs. no)
   4. extrahepatic metastasis (yes vs. no)
3. Alpha fetoprotein(AFP)(≤ 200 ng/mL vs. \> 200 ng/mL) Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive two tablets of sorafenib (200 mg tablets) twice daily (each morning and evening). Patients undergo the first conventional transarterial chemoembolization (TACE) within 3-7 days after the first administration of sorafenib. The conventional TACE consists of an injection containing a mixture of chemotherapeutic agents (doxorubicin) and lipiodol followed by embolization with polyvinyl alcohol (PVA) or beads until complete stasis was achieved in the tumor-feeding vessels. Tumor-feeding vessels should be selected/superselected whenever possible. TACE will be repeated "on demand" depending on the radiological response.

ARM II: Patients receive two tablets of sorafenib (200 mg tablets) twice daily (each morning and evening).

MAINTENANCE THERAPY: Standard follow-up evaluations include contrast-enhanced CT scan and laboratory assessment. Laboratory assessment will be performed every 4 weeks. Radiological follow-up (contrast-enhanced CT scan in liver and chest X-ray) will be performed during week 4 and week 8 after initiation of treatment and thereafter every 8 weeks.

Eligibility Criteria:
Inclusion Criteria:

1. Prior informed consent
2. Advanced stage HCC/ Barcelona Clinic Liver Cancer(BCLC) C stage
3. Confirmed Diagnosis of HCC:

   1. Cirrhotic subjects: Clinical diagnosis by Asian Pacific Association for the Study of the Liver(AASLD) criteria.
   2. Non-cirrhotic subjects: for subjects without cirrhosis, histological or cytological confirmation is mandatory
   3. Documentation of original biopsy for diagnosis is acceptable
4. Child Pugh class A without ascites or hepatic encephalopathy
5. Eastern Cooperative Oncology Group(ECOG) Performance Status of 0-1
6. At least one uni-dimensional lesion measurable by CT-scan or MRI according to the RECIST, 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 subjects ≥ 18 years of age
8. Ability to swallow oral medications
9. Life expectancy of at least 12 weeks
10. 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 function 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. Alanine aminotransferase(ALT) and aspartate aminotransferase(AST) \< 5 x upper limit of normal
    7. Blood urea nitrogen(BUN) and creatinine \< 1.5 x upper limit of normal
    8. International normalized ratio(INR) \< 1.7, or prothrombin time（PT） \< 4 seconds above control

Exclusion Criteria:

1. Diffuse HCC or tumor burden ≥50% of liver parenchyma
2. Main portal vein obstruction, vascular invasion in hepatic vein or inferior vena cava
3. Presence of metastasis in biliary tract,brain or bone
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. Other molecular target drugs ongoing or completed \< 4 weeks prior to the baseline scan
8. Prior transarterial embolization or systemic chemotherapy
9. Any ≥ CTC adverse events(AEs) 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 3.0), except for Hepatitis B virus(HBV) and hepatitis C virus(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(within 6 months of randomization)which could affect the evaluation of the study drug
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