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Sorafenib as Inhibitor of Collateral Tumor Vessel Growth During Transarterial Chemoembolisation (TACE) for Hepatocellular Carcinoma (HCC)- a Pilot Trial to Evaluate Safety and Biological Response

Phase 1/Phase 2
18 Years
Not Enrolling
Hepatocellular Carcinoma

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Trial Information

Sorafenib as Inhibitor of Collateral Tumor Vessel Growth During Transarterial Chemoembolisation (TACE) for Hepatocellular Carcinoma (HCC)- a Pilot Trial to Evaluate Safety and Biological Response

Hepatocellular carcinoma (HCC) as the third most common cause of cancer-related death has a
very poor prognosis.

Aim 1: Efficacy of Sorafenib in combination with TACE TACE is an established therapy for
patients with unresectable HCC and has been shown to significantly improve survival in these
patients compared to no treatment. 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 leading to
tumor recovery and proliferation. Inhibition of this neoangiogenetic and proliferation
activity after TACE by the multikinase inhibitor Sorafenib, already approved for HCC, could
lead to significantly improvement in tumor control and survival in patients with advanced
stage HCC.Safety will be compared with a historical TACE-only group of a placebo controlled

Aim 2: Safety of Sorafenib in combination with TACE:

So far there are no reports about the safety of Sorafenib in combination with TACE. Here we
evaluate the safety and tolerability of this combination until 12 weeks after the last TACE.

Aim 3: PPG-Measurement:

Development of portal hypertension in cirrhosis occurs due to two main pathophysiologic
mechanisms: the increase in resistance to portal blood flow resulting from increased
intrahepatic resistance and the decreased arteriolar vascular tone in the splanchnic
vascular bed leading to increased splanchnic inflow of blood. Very recently, it has been
shown that increased splanchnic inflow does not only result from arteriolar vasodilation due
to excess NO-production in the splanchnic vascular bed but also from an increase in
neoangiogenesis in the splanchnic circulation. Increased neovessel formation occurred within
a few days of onset of portal hypertension both in a cirrhotic and an extrahepatic murine
model of portal hypertension. Neoangiogenesis was effectively inhibited by either an
antibody against VEGF-R2 or an inhibitor of VEGF-R2 autophosphorylation, resulting in a
reduction of splanchnic blood flow.

Most recently, a combination of a VEGF and a PDGF blocker further decreased portal pressure
in an experimental preclinical model.

As Sorafenib is a VEGF and PDGF blocker, we aim to analyze the influence of Sorafenib on
portal hypertension and systemic and hepatic hemodynamics.

Aim 4: Biomarkers for treatment response:

Furthermore, we aim to analyze methylated tumor DNA in serum of patients with HCC undergoing
Sorafenib treatment and TACE as possible marker of treatment response.

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)

- Child-Pugh Stage A or 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 Sorafenib.

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)

- 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:

- Extrahepatic 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

- 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 study entry), myocardial infarction (
≤ 6 months prior to study entry), unstable angina, New York Heart Association (NYHA)
grade II or greater congestive heart failure, serious cardiac arrhythmia requiring

- 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 Sorafenib/TACE or patient at high risk from treatment

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Time to Progression (Efficacy)

Outcome Time Frame:

Until disease progression

Safety Issue:


Principal Investigator

Markus Peck-Radosavljevic, Prof. Dr.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Abteilung Gastroenterologie und Hepatologie, Medizinische Universität und AKH Wien


Austria: Agency for Health and Food Safety

Study ID:




Start Date:

September 2008

Completion Date:

November 2010

Related Keywords:

  • Hepatocellular Carcinoma
  • hepatocellular carcinoma
  • sorafenib
  • transarterial chemoembolization
  • tumor angiogenesis
  • angiogenic factors
  • Carcinoma
  • Carcinoma, Hepatocellular