Clinical Trials Register

Summary
EudraCT Number:	2010-018501-10
Sponsor's Protocol Code Number:	BAY 43-9006 / 12444
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:	2011-02-03
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

2010-018501-10

A.3

Full title of the trial

A Phase III Randomized, Double blind, Placebo-controlled Trial Comparing Capecitabine Plus Sorafenib Versus Capecitabine Plus Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer

A.3.2

Name or abbreviated title of the trial where available

Resilience

A.4.1

Sponsor's protocol code number

BAY 43-9006 / 12444

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
B.1.3.4	Country	Germany
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 Schering Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	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.3.9.1	CAS number	475207-59-1
D.3.9.2	Current sponsor code	BAY 43-9006
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	Comparator
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	Xeloda
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
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	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	Capecitabine
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	150
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

Locally advanced or metastatic HER2-negative breast cancer.

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	10004244

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objective of this phase-III trial is to compare the efficacy and safety of sorafenib in combination with capecitabine versus capecitabine in combination with placebo in the treatment of subjects with locally advanced or metastatic HER2-negative breast cancer who are resistant to or have failed prior taxane and an anthracycline or for whom further anthracycline therapy is not indicated. The primary efficacy endpoint is progression-free survival (PFS).

E.2.2

Secondary objectives of the trial

Secondary efficacy endpoints are overall survival (OS), time to progression (TTP), overall response rate (ORR) and duration of response (DoR). Patient reported outcomes (PROs) include an evaluation of breast cancer symptoms using the Functional Assessment of Cancer Therapy-Breast Symptom Index (8 item) (FBSI-8) questionnaire and health-related quality of life (HRQoL) using the EuroQoL 5 Dimension Questionnaire. Safety evaluations comprise adverse event reporting and assessment of laboratory abnormalities. In addition, this trial includes an exploratory analysis of biomarkers and estimation of capecitabine, 5-FU, and sorafenib exposures.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age is ≥18 years. • Life expectancy is at least 12 weeks (3 months). • Subject has histologically or cytologically confirmed HER2-negative adenocarcinoma of the breast. HER2 status should be determined by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or chromogenic in situ hybridization (CISH). If the subject’s HER2 status was determined using a test kit that is not approved by an appropriate regulatory authority (eg, US Food and Drug Administration) and/or was not tested using a validated assay, HER2 status will be confirmed, with the subject’s consent, using an approved test kit and/or validated assay. If such a subject does not consent to re-testing, the subject will not be eligible for the study. •Subject has locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent (Stage IIIb or IIIc; American Joint Committee on Cancer [AJCC] Staging System, Sixth Edition). •Subject has measurable or non-measurable (but clinically evaluable) disease (according to RECIST 1.1). •All scans used to document disease were done ≤ 4 weeks before randomization. •Subjects are resistant to or have failed a taxane and an anthracycline or for whom further anthracycline therapy is not indicated. oPrior treatment must have included both a taxane (eg, paclitaxel or docetaxel) and an anthracycline (eg, doxorubicin or epirubicin). oThese agents may have been given as either monotherapy or as part of a combination with another agent and may have been included in the same regimen. oSequential neo-adjuvant or adjuvant regimens will count as a single regimen. oThese agents may have been given in either the neo-adjuvant/adjuvant or the metastatic setting or both. oResistance is defined as: -tumor progression while on taxane or within 4 months of last taxane dose when given in the metastatic setting OR •tumor progression while on anthracycline or within 3 months of last anthracycline dose when given in the metastatic setting OR -recurrence within 12 months of the last taxane or anthracycline dose when given in the adjuvant or neo-adjuvant setting. oSubjects for whom further anthracycline is not indicated; such subjects must have received cumulative doses of 400 mg/m2 to 550 mg/m2 of doxorubicin or doxorubicin equivalents (eg, epirubicin). oNote: Subject must meet at least one of the following scenarios to be eligible for the study: -Resistant to or have failed prior taxane and anthracycline (as defined above). -Resistant to or have failed prior taxane and for whom further anthracycline therapy is not indicated (as defined above). •Subject must have received no more than one chemotherapy regimen for metastatic disease. oSubject must have received prior taxane and an anthracycline in the neo-adjuvant/adjuvant setting or metastatic setting. •Prior hormonal therapy for locally advanced or metastatic breast cancer is allowed. •Prior neo-adjuvant or adjuvant chemotherapy is allowed. •Subject must have discontinued prior chemotherapy, prior radiation therapy, or prior hormonal therapy for locally advanced or metastatic disease for greater than or equal to 4 weeks before randomization. Previously radiated areas must not be the only site of disease. •Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. •Creatinine clearance greater than or equal to 50 ml/min (based on Cockcroft-Gault formula).

E.4

Principal exclusion criteria

• Subject must NOT have o active or clinically significant cardiac disease. o thrombotic, embolic, venous, or arterial events within 6 months before randomization. o pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or above within 4 weeks before randomization. o any other hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or above within 4 weeks before randomization.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable will be progression free survival, measured from the date of randomization to the date of first observed disease progression (radiological assessment according to RECIST 1.1 criteria for progression of non-measurable and measurable disease) or the date of death due to any cause (if death occurs before disease progression).

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

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Randomized, Double-blind, placebo controlled

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

100

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

For each participating EU country, the end of the trial according to the EU Clinical Trial Directive will be reached when the last visit (ie, end-of-treatment visit) for the last subject for all centers in the respective country has occurred.

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

E.8.9.2

In all countries concerned by the trial days

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)	No
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	35
F.4.2	For a multinational trial
F.4.2.1	In the EEA	300
F.4.2.2	In the whole clinical trial	519

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

2011-02-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-01-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-10-20

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