TACE Plus Recombinant Human Adenovirus for Hepatocellular Carcinoma

Phase Ⅲ Trial of Transcatheter Arterial Chemoembolization(TACE) Plus Recombinant Human Adenovirus Type 5 Injection for Unresectable Hepatocellular Carcinoma (HCC)

The purpose of this study is to determine if TACE plus Recombinant Human Adenovirus Type 5 Injection will improve outcome in patients with advanced hepatocellular carcinoma (HCC) not amenable to surgery or local ablative therapy.

Transarterial chemoembolization (TACE) is currently one of the mainstays of palliative treatments worldwide for patients with unresectable Hepatocellular Carcinoma(HCC).However, the long term outcomes were generally poor for HCC patients treated with TACE. Recombinant Human Adenovirus Type 5, an E1B gene deleted adenovirus, is known to have a significant antitumor activity. In addition, local injection of recombinant human adenovirus type 5 can enhance the effect of antitumor therapies (chemotherapy and radiotherapy). The hypothesis is that patients with unresectable HCC may benefit from recombinant human adenovirus type 5 in combination with TACE.

Inclusion Criteria:

• Patients newly diagnosed as HCC according to European Association for Study of the Liver criteria.

• BCLC stage A or B

• Child-Pugh class A or B (Child-Pugh score 7)

• ECOG performance status of 0

• Patients must have at least one tumor lesion that meets both of the following criteria:

  • The lesion can be accurately measured in at least one dimension according to RECIST criteria
  • The lesion has not been previously treated with surgery, radiation therapy, radiofrequency ablation, percutaneous ethanol or acetic acid injection, or cryoablation.
  • Patients who have received previous local therapy treatments (RFA, PEI, cryoablation, surgery, resection) to non-target lesions are eligible
  • Local therapy must have been completed at least 4 weeks prior to baseline scan.

• Haematology:Absolute neutrophil count (ANC) > 1 x 109/L, Platelet count > 40 x 109/L, Haemoglobin > 9 g/dL (may be transfused to maintain or exceed this level) Prothrombin time international normalized ratio < 1.5

• Biochemistry:Total bilirubin < 2 mg/dL Serum creatinine < 1.5 x the upper limit of normal

• Ability to understand the protocol and to agree to and sign a written informed consent document

Exclusion Criteria:

• Tumor factors

  • Presence of extrahepatic metastasis
  • Predominantly infiltrative lesion
  • Diffuse tumor morphology with extensive lesions involving both lobes.

• Vascular complications

  • Hepatic artery thrombosis, or
  • Partial or complete thrombosis of the main portal vein, or
  • Tumor invasion of portal branch of contralateral lobe, or
  • Hepatic vein tumor thrombus, or
  • Significant arterioportal shunt not amenable to shunt blockage

• Liver function

  • Advanced liver disease: ascites, hepatic encephalopathy
  • Patients with clinically significant gastrointestinal bleeding within the 30 days prior to study entry.

• Others

  • Renal failure requiring hemo- or peritoneal dialysis

  • Pregnant or lactating women.

  • Active sepsis or bleeding.

  • Hypersensitivity to intravenous contrast agents.

  • The patient has received prior treatment for HCC target lesion.

  • History of cardiac disease

    • Congestive heart failure > NYHA class 2; active coronary artery disease
    • Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin.

  • Hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management.

  • Serious non-healing wounds (including wounds healing by secondary intention), acute or non-healing ulcers, or bone fractures within 3 months.

  • The patient is, in the opinion of the investigator, unable and / or unwilling to comply with treatment and study instructions.

  • Substance abuse (current), psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.

  • Any active clinically serious infections (> grade 2 NCI-CTCAE ver 3.0)

  • HIV infection or AIDS-related illness or serious acute or chronic illness (based on medical history)