A Phase II randomized, double-blind, placebo-controlled study of sorafenib or placebo in combination with transarterial chemoembolisation (TACE) performed with DC Bead and doxorubicin for intermediate stage hepatocellular carcinoma (HCC). - Sorafenib or Placebo in combination with TACE for intermediate HCC (SPACE)

• Register: EUCTR
• Last refreshed on: 20 May 2013
• Main ID: EUCTR2008-005056-24-AT
• Date of registration: 03/02/2009
• Prospective Registration: Yes
• Primary sponsor: Bayer HealthCare AG, 51368 Leverkusen, Germany
• Public title: A Phase II randomized, double-blind, placebo-controlled study of sorafenib or placebo in combination with transarterial chemoembolisation (TACE) performed with DC Bead and doxorubicin for intermediate stage hepatocellular carcinoma (HCC). - Sorafenib or Placebo in combination with TACE for intermediate HCC (SPACE)
• Scientific title: A Phase II randomized, double-blind, placebo-controlled study of sorafenib or placebo in combination with transarterial chemoembolisation (TACE) performed with DC Bead and doxorubicin for intermediate stage hepatocellular carcinoma (HCC). - Sorafenib or Placebo in combination with TACE for intermediate HCC (SPACE)
• Date of first enrolment: 13/03/2009
• Target sample size: 300
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-005056-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Belgium, France, Germany, Italy, Spain

Key inclusion & exclusion criteria

Inclusion criteria:
• Prior informed consent
• Unresectable, multinodular asymptomatic tumor without vascular invasion or extrahepatic spread
• Confirmed Diagnosis of HCC:
- Cirrhotic subjects: Clinical diagnosis by AASLD criteria: HCC can be defined in cirrhotic subjects by one imaging technique (CT scan, MRI, or second generation contrast ultrasound) showing a nodule larger than 2 cm with contrast uptake in the arterial phase and washout in venous or late phases or two imaging techniques showing this radiological behavior for nodules of 1-2 cm in diameter.
Cytohistological confirmation is required for subjects who do not fulfill these eligibility criteria.
- Non-cirrhotic subjects: For subjects without cirrhosis, histological or cytological confirmation is mandatory. Documentation of original biopsy for diagnosis is acceptable
• Child Pugh class A without ascites
• ECOG Performance Status of 0 (see appendix 10.9)
• At least one uni-dimensional lesion measurable according to the RECIST criteria (see appendix 10.8) by CT-scan or MRI
• Male or female subjects = 18 years of age
• Ability to swallow oral medications
• Life expectancy of at least 12 weeks
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment (assessed centrally)
• Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 4 weeks after the completion of trial
• Adequate bone marrow, liver and renal function as assessed by central lab from samples approximately within 7 days prior to randomization.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
• Diffuse HCC or presence of vascular invasion (including segmental portal
obstruction), extrahepatic spread
• Patients on a liver transplantation list or advanced liver disease: Child Pugh B and C, Encephalopathy or ascites
• Any contraindications for hepatic embolization procedures: Known Hepatofugal blood flow, Known Porto-systemic shunt, Impaired clotting test (platelet count < 60000/mm3, prothrombin activity < 50%), Renal failure / insufficiency requiring haemo-or peritoneal dialysis, Known severe atheromatosis
• Lesion having previously been treated with local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) or cryoablation can not be selected as the target lesions.
•Subjects who have received local treatment prior to TACE are only eligible if performed on a different lesion to the one targeted in this study
• Local therapies ongoing or completed < 4 weeks prior to the baseline scan
• Any = CTC AE grade 2 acute toxic effects of any prior local treatment
• History of cardiac disease: Congestive heart failure >New York Heart Association (NYHA) class 2, Active coronary artery disease (CAD) (myocardial infarction more than 6 months prior to study entry is allowed), Cardiac arrhythmias (>Grade 2 NCI-CTCAE Version 3.0) which are poorly controlled with anti-arrhythmic therapy or requiring pace maker, Uncontrolled hypertension
• Known history of HIV infection
• Active clinically serious infections (> grade 2 NCI-CTCAE Version 3.0), except for HBV and HCV infection
• Clinically significant gastrointestinal bleeding within 4 weeks prior to start of study drug
• Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months prior to the first dose of study drug
• Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, T1). Any cancer curatively treated >3 years prior to entry is permitted
• Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results
• Known or suspected allergy to the investigational agent or any agent given in association with this trial
• Any contraindication for sorafenib or doxorubicin administration
• Pregnant or breast-feeding subjects
• Any disease which could affect the evaluation of the study drug
• Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study
• Gastrointestinal disease which could affect the absorption or pharmacokinetics of the study drug
• Subjects unable to swallow oral medications. This includes subjects with severe obstruction of the upper GI tract that require gavage
• Investigational drug or device therapy outside of this trial during or within 4 weeks of study entry (signing informed consent)
• Prior transarterial embolization (with or without chemotherapy)
• Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, MEK inhibitors or farnesyl transferase inhibitors
• Prior use of anthracyclines (e.g. doxorubicin)
• Major surgery within 4 weeks prior to start of study drug (e.g. thoracolaparotomy is not allowed, but noninvasive surgery, e.g. biopsy, is allowed)
• Radiotherapy for HCC during study or before start of study drug
• Use of biologic response

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

This study will evaluate the efficacy and safety of TACE (transarterial chemoembolization) performed with DC Bead and doxorubicin plus sorafenib versus TACE performed with DC Bead and doxorubicin plus placebo for the treatment of intermediate stage HCC.
MedDRA version: 9.1 Level: LLT Classification code 10019828 Term: Hepatocellular carcinoma non-resectable

Intervention(s)

Trade Name: NEXAVAR
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sorafenib
CAS Number: 284461-73-0
Current Sponsor code: BAY-43-9006
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Doxorubin 0.2%
Product Name: Doxorubicin
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DOXORUBICIN HYDROCHLORIDE
CAS Number: 25316409
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Main Objective: To demonstrate the superiority of sorafenib over placebo with regard to Time To Progression (TTP) in patients with intermediate stage HCC receiving TACE performed with DC Bead

Primary end point(s): Primary efficacy objective: Time to progression (TTP) - defined as the time from randomization to radiological disease progression.

Secondary Objectives:
•Overall survival (OS) - defined as the time from randomization to death due to any cause. OS of subjects alive at the time of analysis will be censored at their last data of follow-up.
•Time to untreatable progression (TTUP) - defined as the time from randomization to untreatable progression defined by at least one of the following:
- Failure to achieve objective response after at least 2 TACE sessions in the treated tumor nodule.
- Appearance of contraindications according to selection criteria: this includes vascular invasion, extrahepatic spread and evolution to sustained ascites development (not merely after therapy or coinciding with any adverse event) or to Child Pugh B.
- Clinical progression to ECOG Performance Status > 2
• Time to vascular invasion/extrahepatic spread is defined as time from randomization to the radiological evidence of vascular invasion/extrahepatic spread confirmed by CT/MRI scan.
• Response rate is defined as the percentage of subjects achieving either a confirmed complete or partial tumor response according to RECIST amendment.

Other Objectives:
• Patient reported outcome (PRO) as measured by FACT-Hep and EQ-5D
• Evaluation of Biomarkers

Secondary Objective: • Overall Survival (OS)
• Time to untreatable progression (TTUP)
• Time to vascular invasion / extrahepatic spread
• Safety
• Patient-Reported Outcome (PRO) as assessed by FACT-Hep and EQ-5D questionnaire
• Evaluation of biomarkers
• Response Rate (RECIST Amendment)

Secondary ID(s)

BAY 43-9006 / 12918