Clinical Trial for GALNT14 Genotype - Guided, Sorafenib in Combination With TACE in Hepatocellular Carcinoma

Transcatheter arterial chemoembolization (TACE) + sorafenib therapy has been demonstrated to exert a beneficial effective on time-to-tumor-progression (TTP) in patients with unresectable hepatocellular carcinoma (HCC) in some studies. However, the beneficial effect varies among studies conducted in different areas of the world. The objectives of this study are (1) to understand whether GALNT14 TT genotype patients respond better than do GALNT14 non-TT genotype patients when treated by TACE; and (2) to understand whether GALNT14 non-TT genotype patients can benefit from TACE plus sorafenib (Nexavar) combination therapy. Patients enrolled will be stratified by GALNT14 genotyping. The GALNT14 "non-TT" patients were then randomized into two subgroups to evaluate the safety, tolerability and efficacy of TACE plus sorafenib therapy.

The primary endpoint of this study is the efficacy of TACE with or without sorafenib combination therapy evaluated by complete remission (CR).

The secondary endpoints are:

1. Time to partial or complete response (PR + CR).
2. Time-to-tumor-progression (TTP) and the progression free survival (PFS).
3. Overall survival (OS).
4. Safety and tolerability of TACE plus sorafenib therapy.

The strategy of TACE + sorafenib is now being intensively investigated. It is a safe approach with significant beneficial effect on TTP in some studies, but the beneficial effect on OS remains uncertain. In the present study, we hypothesized that the GALNT14 genotype might play a role in this issue. Our pilot study indicated that GALNT14 "TT" genotype was associated with a favorable complete response rate in patients treated by TACE alone. This genotype was present in \~ 25% of Chinese population coming from Taiwan, Colorado (US), or Beijing (China), and in \~ 7% of Italian population. But it was present in \~ 50% of Japanese population. The lower percentage of a TACE - favorable genotype in Chinese and Italian population could explain the different results between Japanese and Chinese/Italian clinical trials. It is possible that in a population with higher percentage of TACE - favorable genotype (GALNT14 "TT"), the beneficial effect of sorafenib adjuvant treatment might not be detected. In this study, we proposed to examine the TACE + sorafenib effect in patients with GALNT14 "non-TT" genotype, a TACE - unfavorable genotype.

Eligibility Criteria:
Inclusion Criteria:

1. Confirmed Diagnosis of HCC:

   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 2cm with contrast uptake in the arterial phase and washout in venous or late phases, or two imaging techniques showing this radiological behaviour for nodules of 1-2cm in diameter Cytohistological confirmation is required for subjects who do not fulfill these eligibility criteria

   Non-cirrhotic subjects:

   For subjects without cirrhosis, histological confirmation is mandatory Documentation of original biopsy for diagnosis is acceptable
2. Never received TACE/ chemotherapy/ radiotherapy or targeted agents prior to this study.
3. Patients should be either in BCLC clinical stage B (multinodular asymptomatic tumors without extra-hepatic spread or portal vein invasion) with or without unilateral secondary or tertiary branches of portal vein invasion. Main portal vein invasion or extra-hepatic spread is not allowed.
4. Child-Pugh functional class A or B.
5. Measurable disease using mRECIST criteria. At least 1 measurable lesion must be present.
6. ECOG performance status 0 to 1.
7. Age \> 18 years
8. Both men and women enrolled in this trial must use adequate birth control measures during the course of the trial and 4 weeks after the completion of trial
9. Informed consent must be obtained prior to study initiation.
10. Total bilirubin \< 3.0 mg/dL with no evidence of biliary tract obstruction.
11. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 5 × upper limit of normal.
12. Absolute neutrophil count \> 1000/mm3; Platelets ≧ 60x109/L.
13. Serum creatinine \< 2 x ULN.
14. Antiviral treatment for hepatitis B or C is allowed except for interferon.

Exclusion Criteria:

1. BCLC stage A.
2. Presence of extrahepatic metastasis.
3. Child-Pugh score =C
4. Significant cardiac disease.
5. Serious bacteria infection requiring systemic antibiotics.
6. Pregnancy
7. Expected non-compliance.
8. Uncontrolled illness including, but not limited to, ongoing infection, congestive hear failure, unstable angina pectoris, cardiac arryhythmia, or psychiatric illness.
9. Bleeding esophageal or gastric varices within three months without ligation or sclerosis injection therapy.
10. Subjects with known HIV infection.
11. ECOG status \> or = 2