Clinical Trials Register

Summary
EudraCT Number:	2008-006872-31
Sponsor's Protocol Code Number:	MO22223
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2009-03-27
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

Spain - AEMPS

A.2

EudraCT number

2008-006872-31

A.3

Full title of the trial

Estudio fase III randomizado de bevacizumab más capecitabina versus bevacizumab solo, como tratamiento de mantenimiento en pacientes con cáncer de mama metastático HER2-negativo que no hayan progresado durante el tratamiento de primera línea con docetaxel más bevacizumab .
A randomized phase III clinical study of bevacizumab plus capecitabine vs. bevacizumab alone as maintenance therapy in patients with HER2-negative metastatic breast cancer that has not progressed during first-line docetaxel plus bevacizumab therapy.

A.3.2

Name or abbreviated title of the trial where available

IMELDA

A.4.1

Sponsor's protocol code number

MO22223

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	F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
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	AVASTIN 25 mg/ml concentrado para solución para perfusión
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.3	Other descriptive name	BEVACIZUMAB
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
D.3.11.13.1	Other medicinal product type	Recombinant humanised monoclonal antibody
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	XELODA 500 mg comprimidos recubiertos con película
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	CAPECITABINA
D.3.9.1	CAS number	154361-50-9
D.3.9.3	Other descriptive name	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	500
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: 3
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	AVASTIN 25 mg/ml concentrado para solución para perfusión
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.3	Other descriptive name	BEVACIZUMAB
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
D.3.11.13.1	Other medicinal product type	Recombinant humanised monoclonal antibody

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Tratamiento de pacientes con cáncer de mama metastático negativo para HER-2 que no han manifestado progresión durante el tratamiento de primera línea con docetaxel más bevacizumab. HER2-negative metastatic breast cancer that has not progressed during first-line docetaxel plus bevacizumab therapy.

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	10055113
E.1.2	Term	Breast cancer metastatic

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate whether maintenance therapy with bevacizumab plus capecitabine, compared to bevacizumab alone, can further increase Progression-Free Survival (PFS) in patients showing objective response or stable disease following initial therapy with bevacizumab plus docetaxel.

E.2.2

Secondary objectives of the trial

To evaluate the following parameters:
During the initial treatment phase:
? Overall Response Rate (ORR)
? Clinical Benefit Rate (CBR)
? Safety and tolerability
During the Maintenance treatment phase:
? ORR
? CBR
? Quality of life
? Time-to-Progression (TTP)
? Overall Survival (OS)
? Safety and tolerability

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Initial treatment phase:
1. Signed informed consent obtained prior to initiation of any study specific procedures or treatment as confirmation of the patient?s awareness and willingness to comply with the study requirements
2. Age ? 18 years
3. Patients with histologically confirmed and documented, HER2-negative metastatic adenocarcinoma of the breast, who are candidates for taxane-based chemotherapy
4. Documented ER/PgR status
5. ECOG PS of 0-1;
6. Life expectancy of ? 12 weeks
Maintenance treatment phase:
1. Patients must have SD, PR or CR per RECIST by the end of the initial treatment phase with bevacizumab plus docetaxel. Those patients who meet the response criteria at cycle 6 can be immediately randomised into the maintenance treatment phase (without needing to wait for results a confirmatory scan). Note: in the event that a patient is found to be responding at cycle 3 but is experiencing toxicities that would require a dose-interruption, investigators can use their discretion to immediately randomise the patient to the maintenance treatment phase.

E.4

Principal exclusion criteria

1. Previous chemotherapy for mBC. Prior hormone therapy for metastatic disease is allowed.
2. Prior adjuvant/neoadjuvant chemotherapy within 6 m. prior to first study treatment administration.
3. Prior adjuvant/neoadjuvant anthracycline-based chemotherapy with a max. cumulative dose >360 mg/m2 for doxorubicin or >720 mg/m2 for epirubicin.
4. Prior radiotherapy for the treatment of metastatic disease. Radiotherapy administered for the relief of metastatic bone pain is allowed prior to study entry, as long as no more than 30% of marrow-bearing bone was irradiated.
5. Chronic daily treatment with aspirin (>325 mg/day) or clopidogrel (>75 mg/day).
6. Requirement for concurrent use of the antiviral agent sorivudine, or chemically related analogues, such as brivudine.
7. Chronic daily treatment with corticosteroids (dose of ?10 mg/day methylprednisolone or equivalent), with the exception of inhaled steroids.
8. Current or recent treatment with another investigational drug or participation in another investigational study.
9. Inadequate bone marrow function: ANC: <1.5 x 10E9/l, platelet count <100 x 10E9/l or haemoglobin <8 g/dl.
10. Inadequate liver function, defined as:
? serum (total) bilirubin >1.5 x ULN for the institution
? AST/SGOT or ALT/SGPT >2.5 x ULN (>5 x ULN in patients with liver metastases)
? ALP >2.5 x ULN at baseline (>5 x ULN in patients with liver metastases, or >10 x ULN in patients with bone metastases).
11. Inadequate renal function, defined as:
? serum creatinine >1.5 x ULN
? creatinine clearance <50 ml/min (calculated according to Cockroft and Gault)
? urine dipstick for proteinuria >2+. Patients with ?2+ proteinuria on dipstick analysis at baseline should undergo a 24-hour urine collection and must demonstrate ?1g of protein in the 24-hour urine.
12. Patients not receiving anticoagulant medication who have an INR >1.5 or an aPTT >1.5 x ULN within 7 days prior to first study treatment.
13. Evidence of spinal cord compression or brain metastases.
14. Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer.
15. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.
16. Women of childbearing potential (defined as <2 years after last menstruation and not surgically sterile) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly).
17. Major surgical procedure within 28 days prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment.
18. Minor surgical procedures, within 24 hours prior to the first study treatment.
19. History of uncontrolled seizures, CNS disorders or psychiatric disability judged by the Investigator to be clinically significant precluding informed consent or interfering with compliance for oral drug intake.
20. Pre-existing peripheral neuropathy >CTC grade 2.
21. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
22. Uncontrolled hypertension (systolic >150 mm Hg and/or diastolic >100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident (CVA)/stroke within ?6 months prior to the first study treatment, myocardial infarction within ?6 months prior to the first study treatment, unstable angina, NYHA grade II or greater CHF, or serious cardiac arrhythmia requiring medication.
23. History of abdominal fistula, grade 4 bowel obstruction or gastrointestinal perforation, intra-abdominal abscess within 6 months prior to randomisation.
24. Lack of physical integrity of the upper gastrointestinal tract, clinically significant malabsorption syndrome, or inability to take oral medications.
25. Serious non-healing wound, peptic ulcer or bone fracture.
26. Serious active infection requiring i.v. antibiotics at enrolment.
27. Prior unanticipated severe reaction to fluoropyrimidine therapy.
28. Known dihydropyrimidine dehydrogenase deficiency.
29. Known hypersensitivity to any of the study treatments or excipients.
30. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanised antibodies.
31. Evidence of any other medical conditions that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is PFS, defined as the time from first study drug dosing (during the maintenance treatment phase) to the first documented disease progression or death, whichever occurs first. Progression will be based on tumour assessment made by the investigators according to the RECIST criteria. In this trial, PFS will be used to evaluate whether maintenance therapy with bevacizumab plus capecitabine compared to bevacizumab alone, further improves the response to treatment following initial therapy with bevacizumab plus docetaxel.

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability; Markers of predictive value: ER/PgR; HER-2; Quality of life

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

bevacizumab en monoterapia

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

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

Patient will be followed-up every 3 months after PD is documented. Each patient will be followed for 12 months for PFS and at least 24 months after the last patient have been enrolled.

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	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
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	No
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	25
F.4.2	For a multinational trial
F.4.2.1	In the EEA	170
F.4.2.2	In the whole clinical trial	420

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

2009-05-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-05-05

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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