Transcatheter Arterial Chemoembolization Therapy In Combination With Sorafenib

Phase II Study: Transcatheter Arterial Chemoembolization Therapy In Combination With Sorafenib (TACTICS)

The purpose of this study is to evaluate the safety and efficacy of the combination therapy with Transcatheter Arterial Chemoembolization (TACE) and sorafenib compared to TACE alone in patients with unresectable hepatocellular carcinoma (HCC) who are not candidates for surgical resection or percutaneous ablation therapy.

TACE with sorafenib Group

Sorafenib will be administrated at a dose of 400mg o.d. before the first TACE. After 2days drug rest, TACE will be conducted. Sorafenib will be resumed at a dose of 400mg o.d. from 3 days after TACE(the resumption day can be postponed until 21 days after TACE). When tolerability is confirmed at 1 week after resumption, the dose of sorafenib will be increased to 400mg b.i.d. When tumor increases, TACE will be repeated.

Control group

TACE will be conducted at scheduled day. When tumor increases, TACE will be repeated.

The treatment regimen will be continued until untreatable progression which is defined as follows:

• Child-Pugh grade C
• Tumor growth (125 percent from baseline status)
• Vascular invasion(Vp3,Vp4)
• Extra hepatic spread which size is more than 10mm

Inclusion Criteria:

1. Patients aged 20 Years or over

2. Patients who were fully informed of the study beforehand and signed the informed consent to participate in the study.

3. Patients who are expected to live more than 12 weeks.

4. Patients diagnosed with typical HCC by biopsy,cytology, or diagnostic imaging such as dynamic CT(MRI).Typical HCC is defined by AASLD criteria.

5. Patients in whom complete resection of the tumor by hepatectomy or complete tumor necrosis by local tumor necrosis therapy(RFA) cannot be expected to succeed.

6. Patients with tumors which are confirmed to the liver and can be treated by TACE(the maximum diameter equal to or less than 10cm,and the maximum number of nodule equal to or less than 10).

7. Patients with viable and measurable target lesion.

8. patients with no or one history of TACE therapy.

9. patients with an ECOG PS(Performance Status) Score of 0 or 1.

10. patients with Child-Pugh class A.

11. Patients with laboratory values that meet the following criteria:

    1. Hemoglobin ≥ 8.5 g/dl
    2. Granulocytes ≥ 1500/mm3
    3. Platelet count ≥ 50,000 /mm3
    4. Total serum bilirubin ≤ 3 mg/dl
    5. AST and ALT ≤ 6 times upper limits of normal
    6. Serum creatinine ≤ 1.5 times upper limits of normal

Exclusion Criteria:

1. History of malignant tumor, excluding the following cases:

   1. Curatively treated early stage cancer with a low risk of recurrence ,such as carcinoma in situ of the cervix, basal cell carcinoma, superficial bladder tumor, and early gastric cancer.
   2. Malignant tumor that was curatively treated more than 3 years prior to study entry and has not recurred since then

2. Cardiac disease that meet any of the following criteria:

   1. NYHA Class III or higher congestive heart failure
   2. History of symptomatic coronary artery disease or myocardial infarction within 6 months before enrollment
   3. Arrhythmia requiring control by antiarrhythmic drugs such as beta-blockers or digoxin

3. Serious and active infection, except for HBV and HCV

4. History of HIV infection

5. Renal dialysis

6. Diffuse tumor lesion

7. Extrahepatic metastasis

8. Vascular invasion

9. Intracranial tumor

10. Preexisting or history of hepatic encephalopathy

11. Clinically uncontrolled ascites or pleural effusion

12. Clinically severe gastrointestinal bleeding within 4 weeks of the start of treatment

13. Esophageal and/or gastric varices which has high risk of bleeding

14. History of thrombosis and/or embolism within 6 months of the start of treatment

15. History of receiving any of the following therapies:

    1. Systemic chemotherapy for advanced HCC(including sorafenib therapy)
    2. Local therapy, such as radiofrequency ablation, TACE, or hepatic arterial infusion within 3 months of the start of treatment
    3. Current treatment with CYP3A4 inducing agents
    4. Invasive surgery within 4 weeks of the start of treatment
    5. History of allogenic transplantation
    6. History of bone marrow transplant or haemopoietic stem cell transplant within 4 weeks of the start of this study

16. Unable to take oral medications

17. Gastrointestinal problems that may affect absorption or pharmacokinetics of the study drugs

18. Use of drugs that may affect absorption or pharmacokinetics of the study drugs

19. Concurrent disease or disability that may affect evaluation of the effects of the study drugs

20. Enrollment in another study within 4 weeks of study entry

21. Female patients who are pregnant, lactating, possibly pregnant, or planning to become pregnant

22. Risk of allergic reactions to the study drugs

23. Drug abuse or other physical, psychological , or social problems that may interfere with the participation in the study or evaluation of study results

24. Any condition that could jeopardize the safety of the patient or their compliance in the study