Clinical Trials Register

Summary
EudraCT Number:	2008-005056-24
Sponsor's Protocol Code Number:	12918
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-03-31
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2008-005056-24

A.3

Full title of the trial

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

A.3.2

Name or abbreviated title of the trial where available

SPACE

A.4.1

Sponsor's protocol code number

12918

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bayer HealthCare AG, D-51368 Leverkusen, Germany
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	NEXAVAR
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/06/364
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sorafenib
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Doxorubicin 0.2%
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmachemie B.V.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intraarterial use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Doxorubicin
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

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 Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10019828
E.1.2	Term	Hepatocellular carcinoma non-resectable

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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

E.2.2

Secondary objectives of the trial

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)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Prior informed consent Unresectable, multinodular asymptomatic tumor (no 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 confirmation is mandatory. Documentation of original biopsy for diagnosis is acceptable Child Pugh class A 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 CTscan or MRI Male or female subjects &#8805; 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 7 days prior to randomization.

E.4

Principal exclusion criteria

Diffuse HCC or presence of vascular invasion (including segmental portal obstruction), extrahepatic spread; Advanced liver disease* Any contraindications for hepatic embolization procedures* Target lesion having previously been treated with local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) or cryoablation. 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 &#8805; CTC AE grade 2 acute toxic effects of any prior local treatment History of cardiac disease* 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* Radiotherapy for HCC during study or before start of study drug Use of biologic response modifiers, such as G-CSF, within 3 weeks prior to start of study drug* Autologous bone marrow transplant or stem cell rescue within 1 year prior to start of study drug History of organ allograft Any agents which could affect the absorption or pharmacokinetics of the study drug and doxorubicin * please make reference to the protocol

E.5 End points

E.5.1

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Risultati riportati dai pazienti

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Da un punto di vista normativo, come data di fine studio sara` considerata quella in cui l’ultimo paziente ha completato l’ultima visita di fine trattamento (LPLV). Nota: per maggiori informazioni far rifeimento al protocollo

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	36
F.4.2	For a multinational trial
F.4.2.1	In the EEA	118
F.4.2.2	In the whole clinical trial	300

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-02-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-02-08

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