Safety concerns in the treatment arm

Patients with liver cirrhosis and hepatocellular carcinoma will undergo transarterial chemoembolisation (TACE) as clinically indicated and will be randomized to receive bevacizumab or placebo every 2 weeks up to 1 year. Tumor response will be assessed using MR of the liver and PET-scanning.

It will be tested whether the addition of bevacizumab as angiogenic inhibitor will slow down tumor progression, reduce the need for re-embolisation and will improve patient survival.

TACE is an established therapy for patients with advanced stage HCC not amenable to liver transplantation or resection and has been shown to significantly improve survival in these patients compared to no treatment (8). TACE takes advantage of the predominantly arterial blood supply of malignant liver tumors contrary to the surrounding normal liver tissue, which receives more blood supply through the portal venous system.

TACE leads to predictable tumor necrosis until new blood vessels grow into the tumor margins to support tumor growth. Quite often after cutting off the blood supply through the hepatic artery, the tumor induces active angiogenesis to promote collateral blood vessel growth from liver capsule arteries or collaterals from the gastroduodenal artery. VEGF seems to be an important player in inducing this angiogenetic activity and tumor control and survival of patients after TACE have been linked to serum VEGF-levels with higher levels showing reduced survival.

Inhibition of these neoangiogenetic activity could lead to significantly improved in tumor control and survival in patients with advanced stage HCC.

2. STUDY OBJECTIVE

• to assess the effectiveness of bevacizumab in combination with TACE as measured by patients without tumor progression on MRT after 3 cycles of TACE as well as the number of TACE cycles applied for recurrent tumor after a maximum of one year treatment with bevacizumab
• to assess collateral tumor vessel growth on MRT / CT

Inclusion Criteria:

• Patients with histologically confirmed HCC not suitable for OLT or resection (>3 nodules, >5 cm diameter, vascular invasion, clinically significant portal hypertension, other contraindications against OLT) or patients awaiting OLT with an expected waiting time >12 months

• Child-Pugh Stage A and B

• Liver disease of any etiology

• Written informed consent (approved by the Institutional Review Board [IRB]/Independent Ethics Committee [IEC]) obtained prior to any study specific screening procedures

• Patient must be able to comply with the protocol

• Age ≥18 years

• Women of childbearing potential must have a negative serum pregnancy test done 1 week prior to the administration of the study drug. Fertile women and men of childbearing potential (<2 years after last menstruation in women) must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile)

• Proteinuria at baseline:

  • Urine dipstick of proteinuria <2+. Patients discovered to have >2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate less <= 1 g of protein/24 hr.

• 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 >= 40%

• Biochemistry:

  • Total bilirubin <= 5 mg/dL
  • Serum creatinine < 3.0 mg/dL
  • Life expectancy of >3 months

Exclusion Criteria:

• extra hepatic tumor spread
• complete portal vein thrombosis (common trunk)
• Child-Pugh-Stage C
• Prior TACE or TAE
• Other experimental therapies for HCC
• Acute variceal bleeding within the last 2 weeks
• Large oesophageal varices (>5 mm diameter) without prophylactic band ligation
• Past or current history (within the last 2 years prior to randomisation) of malignancies except for the indication under this study and curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix
• History or evidence upon physical examination of CNS disease unless adequately treated (e.g., seizure not controlled with standard medical therapy or history of stroke within < 6 months), excluding hepatic encephalopathy
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study
• Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants for therapeutic purposes
• Chronic, daily treatment with aspirin (>325mg/day)
• Pregnancy (positive serum pregnancy test) or lactation
• Uncontrolled hypertension
• Serious, non-healing wound, ulcer, or bone fracture
• Patients with known allergy to Chinese hamster ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of Bevacizumab formulation; or to any other study drugs
• Currently or recent (within the 30 days prior to starting study treatment) treatment of another investigational drug or participation in another investigational study
• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤ 6 months prior to randomisation), myocardial infarction (≤ 6 months prior to randomisation), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication
• Evidence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications