Trial document

This trial has been registered retrospectively.
drksid header


Trial Description

start of 1:1-Block title


Intermittent treatment with sorafenib in combination with transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): a randomized open-label phase 2 study

end of 1:1-Block title
start of 1:1-Block acronym

Trial Acronym


end of 1:1-Block acronym
start of 1:1-Block url

URL of the Trial

end of 1:1-Block url
start of 1:1-Block public summary

Brief Summary in Lay Language


end of 1:1-Block public summary
start of 1:1-Block scientific synopsis

Brief Summary in Scientific Language

For patients with advanced HCC not suitable for resection or liver transplantation but without extrahepatic manifestations or total portal vein thrombosis, local therapy with TACE is regarded as standard treatment. However, in the majority of TACE treated patients disease progression is noted as revascularization of treated HCC-nodules, appearance of new HCC-nodules (de-novo HCC), appearance of extra hepatic manifestation or vascular invasion.
Vascular growth factor (VEGF) is a potent regulator of neovascularization contributing to the pathogenesis of HCC [Finn et al. 2009]. Serum VEGF levels are higher in patients with HCC than in patients with endothelial benign liver lesions or healthy controls [Li et al. 2004; Chao et al. 2003]. Furthermore, elevated VEGF levels are a negative prognostic biomarker in HCC [Poon et al. 2004].
TACE up-regulates VEGF through an induction of tumor anoxia and ischemia [Wang et al. 2008]. This upregulation however is transient, with a peak 24 hours after TACE and thereafter a gradually decrease [Li et al. 2004; Sergio et al. 2008]. Given the role of VEGF in HCC, and the changes in VEGF associated with TACE, a pilot study with TACE in combination with systemic treatment using the VEGF antibody bevacizumab was reported [Finn et al. 2012]. In this study, bevacizumab attenuated the post TACE VEGF increase and diminished neovessel formation. However, bevacizumab is not approved for HCC treatment.
Since sorafenib is a dual growth factor and angiogenesis inhibitor, temporary treatment following TACE might prevent the induction of such proangiogenic factors and therefore prevent disease progression. Recently, it has been reported both in human as well as in mice VEGFA-amplified HCC are very responsive to treatment with sorafenib. Therefore dual therapy with TACE and sorafenib is very attractive and a recent meta-analysis also suggested a benefit over TACE alone [Liu et al. 2014]. Since in the SPACE trial using doxorubicin-eluting beads-based TACE together with continuous sorafenib treatment, a substantial proportion of patients were taken off the study due to toxicity before tumor progression [Lencioni et al., 2012], the obvious consequence is to dose sorafenib only for a limited period of time during TACE application. The current randomized study will therefore evaluate the intermittent treatment with sorafenib for 7 days following TACE. The short-term application of sorafenib might me associated with few sorafenib-associated side effects and therefore might be better accepted by patients. In addition to efficacy quality of life will be closely monitored.

end of 1:1-Block scientific synopsis
start of 1:1-Block organizational data

Organizational Data

  •   DRKS00012551
  •   2017/07/12
  •   [---]*
  •   yes
  •   Approved
  •   35/15, Ethikkommission des Fachbereichs Humanmedizin der Johann-Wolfgang-Goethe-Universität Frankfurt am Main
end of 1:1-Block organizational data
start of 1:n-Block secondary IDs

Secondary IDs

  •   2014-005406-38 
end of 1:n-Block secondary IDs
start of 1:N-Block indications

Health Condition or Problem studied

  •   C22.0 -  Malignant neoplasm: Liver cell carcinoma
end of 1:N-Block indications
start of 1:N-Block interventions

Interventions/Observational Groups

  •   TACE ( transarterial chemoembolisation) + intermittent Sorafenib-therapy (for 7 days, starting with TACE-treatment)
  •   TACE treatment
end of 1:N-Block interventions
start of 1:1-Block design


  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   II
  •   No
end of 1:1-Block design
start of 1:1-Block primary endpoint

Primary Outcome

determination of time to progression (TTP) by mRECIST for HCC

end of 1:1-Block primary endpoint
start of 1:1-Block secondary endpoint

Secondary Outcome

Determination of
– overall survival (OS)
– response rate (either complete response, CR, or partial response, as measured by mRECIST for HCC)
– safety profile
– quality of life (as measured by FACT-Hep and EQ-5D questionaires

end of 1:1-Block secondary endpoint
start of 1:n-Block recruitment countries

Countries of Recruitment

  •   Germany
end of 1:n-Block recruitment countries
start of 1:n-Block recruitment locations

Locations of Recruitment

  • University Medical Center 
end of 1:n-Block recruitment locations
start of 1:1-Block recruitment


  •   Actual
  •   2016/12/29
  •   77
  •   Monocenter trial
  •   National
end of 1:1-Block recruitment
start of 1:1-Block inclusion criteria

Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
end of 1:1-Block inclusion criteria
start of 1:1-Block inclusion criteria add

Additional Inclusion Criteria

Written informed consent granted prior to initiation of any study specific screening procedures
– Patients with histologically confirmed HCC not suitable for resection or liver transplantation (> 3 tumors > 3 cm; one tumor > 5 cm). Vascular invasion is allowed as long as the main trunk of the portal vein is not invaded)
– Absence of extrahepatic spread
– Age > 18 years
– Patients with measurable disease according to RECIST
– Performance status ECOG 0 and 1 (Appendix 20)
– Patients naive to treatment with respect to the HCC
– Normal organ and bone marrow function defined as:
– Hematopoetic: absolute neutrophil count > 1,500/mm3, platelet count > 60,000/mm3, hemoglobin > 9g/dL
– INR < 1.5 ULN
– Hepatic: AST or ALT < 5 x ULN, bilirubin ≤ 3 mg/dl
– Renal: serum creatinine < 1.5 x ULN
– Child-Pugh stage A
– Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the randomization
– Male or female patients of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received

end of 1:1-Block inclusion criteria add
start of 1:1-Block exclusion criteria

Exclusion Criteria

Extrahepatic tumor manifestation
– Thrombosis of the main portal vein (thrombosis of a side-branch is allowed)
– Child Pugh status B or C > 6 points according to Child Pugh classification
– Prior TACE or selective intraarterial Radiotherapiy (SIRT)
– Prior systemic anticancer chemotherapy for HCC
– Life expectancy of less than 12 weeks
– Esophageal varices grade III (any) or esophageal varices grade II with increased risk for bleeding (red wale signs, cherry spots, red coloration, hematocystic spots) without prophylactic band ligation
– Cardiac disease: congestive heart failure > class II NYHA, unstable angina or new onset of angina or myocardial infarction within the past 6 months. Cardiac ventricular arrhythmias requiring antiarrhythmic therapy
– Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal management
– Known or suspected hyperthyroid state
– Known brain metastasis. Patients with symptoms should undergo CT/MRT of the brain to exclude brain metastasis
– Patients with seizure disorder requiring medication (such as steroids or antiepileptics)
– History of organ allograft
– Active clinically serious infections > CTCAE grade 2 except chronic hepatitis C infection
– Thrombotic or embolic events including transient ischemic attacks within the past 6 months
– Hemorrhage or bleeding event, CTCAE grade 3 within 4 weeks of first dose of study drug
– Acute variceal bleeding within the last 2 weeks
– Serious non healing wound, ulcer or bone fracture
– Evidence or history of bleeding diathesis or coagulopathy
– Therapeutic anticoagulation with Marcumar, heparins or indirect factor-Xa inhibitors or direct thrombinantagonists. Low dose aspirin is permitted (100 mg per day)
– Major surgery, open biopsy or significant traumatic injury within 4 weeks of first dose of study drug
– Known or suspected allergies to sorafenib, mitomycin C or lipiodol
– Previous cancer that is distinct in primary site or histology from HCC except cervical cancer in situ, treated basal cell carcinoma, superficial bladder tumors or any cancer curatively treated 3 years prior to study entry
– Substance abuse, medical or psychological condition that may interfere with the patient´s participation in the study
– Participation in another clinical trial with any investigational study drug (whatever the use, curative, prophylactic or diagnostic intent) within 30 days prior to enrollment
– Incapability to give valid informed consent (including patients who are dependent on the sponsor or the investigator)
– Pregnancy and breast-feeding women

end of 1:1-Block exclusion criteria
start of 1:n-Block addresses


  • start of 1:1-Block address primary-sponsor
    • Dekanat des Fachbereichs Medizin Klinikum der Johann Wolfgang Goethe-Universität, Haus 1
    • Mr.  Prof. Dr. med.  Josef  Pfeilschifter 
    • Theodor-Stern-Kai 7
    • 60590  Frankfurt am Main
    • Germany
    end of 1:1-Block address primary-sponsor
    start of 1:1-Block address contact primary-sponsor
    end of 1:1-Block address contact primary-sponsor
  • start of 1:1-Block address scientific-contact
    • Universitätsklinikum Frankfurt Medizinische Klinik 1
    • Mr.  Prof. Dr. med.  Jörg  Trojan 
    • Theodor-Stern-Kai 7
    • 60590  Frankfurt
    • Germany
    end of 1:1-Block address scientific-contact
    start of 1:1-Block address contact scientific-contact
    end of 1:1-Block address contact scientific-contact
  • start of 1:1-Block address public-contact
    • Universitätsklinikum Frankfurt Medizinische Klinik 1
    • Mr.  Prof. Dr. med.  Jörg  Trojan 
    • Theodor-Stern-Kai 7
    • 60590  Frankfurt
    • Germany
    end of 1:1-Block address public-contact
    start of 1:1-Block address contact public-contact
    end of 1:1-Block address contact public-contact
end of 1:n-Block addresses
start of 1:n-Block material support

Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Medizinische Klinik 1 Studienambulanz Prof. Zeuzem
    • Theodor-Stern-Kai 7
    • 60590  Frankfurt
    • Germany
    end of 1:1-Block address materialSupport
    start of 1:1-Block address contact materialSupport
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
    end of 1:1-Block address contact materialSupport
end of 1:n-Block material support
start of 1:1-Block state


  •   Recruiting ongoing
  •   [---]*
end of 1:1-Block state
start of 1:n-Block publications

Trial Publications, Results and other Documents

  • [---]*
end of 1:n-Block publications
* This entry means the parameter is not applicable or has not been set.