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    The EU Clinical Trials Register currently displays   35474   clinical trials with a EudraCT protocol, of which   5826   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2006-006507-36
    Sponsor's Protocol Code Number:AVF3693g-A1
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-03-04
    Trial results Removed from public view
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2006-006507-36
    A.3Full title of the trial
    A PHASE III, MULTICENTER, RANDOMIZED,PLACEBO-CONTROLLED TRIAL EVALUATING
    THE EFFICACY AND SAFETY OF BEVACIZUMAB IN COMBINATION WITH CHEMOTHERAPY
    REGIMENS IN SUBJECTS WITH PREVIOUSLY TREATED METASTATIC BREAST CANCER

    Estudio en fase III, multicéntrico, aleatorizado, controlado con placebo para evaluar la eficacia y la seguridad de Bevacizumab en combinación con regímenes de quimioterapia en pacientes con cáncer de mama metastático que hayan sido previamente tratados.
    A.3.2Name or abbreviated title of the trial where available
    Ribbon-2
    A.4.1Sponsor's protocol code numberAVF3693g-A1
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGenentech Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBevacizumab
    D.3.4Pharmaceutical form Intravenous infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBevacizumab
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeRO487-6646
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25mg/ml
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeRecombinant humanised monoclonal antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboIntravenous infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Previously Treated Metastatic Breast Cancer

    Cancer de mama metastásico previamente tratado
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to determine the clinical benefit of the
    addition of bevacizumab to standard chemotherapy for previously treated MBC in
    subjects without brain metastasis as measured by PFS, assessed in a two-step,
    hierarchical manner, as follows:

    • Determination of the clinical benefit, as measured by PFS, of the addition of
    bevacizumab to non-capecitabine therapy, i.e., taxane (docetaxel, paclitaxel,
    paclitaxel protein-bound particles [Abraxane]), gemcitabine, or vinorelbine
    therapy compared with these chemotherapies alone in subjects receiving
    second-line therapy for MBC

    • Determination of the clinical benefit, as measured by PFS, of the addition of
    bevacizumab to any protocol-allowed chemotherapy (taxane, capecitabine,
    gemcitabine, or vinorelbine) compared with chemotherapy alone in subjects
    receiving second-line therapy for MBC
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate the efficacy and safety of
    bevacizumab when combined with chemotherapy compared with chemotherapy
    alone in subjects without brain metastasis receiving second-line therapy for MBC,
    as measured by the following:

    • Estimation of the clinical benefit of the addition of bevacizumab to each chemotherapy
    regimen, with PFS estimates and confidence limits calculated within each
    chemotherapy stratum for bevacizumab and placebo

    • Determination of the clinical benefit, as measured by objective response rate, duration of objective response, one-year survival, and overall survival, of the addition of bevacizumab to standard chemotherapy options compared with standard
    chemotherapy alone

    • Comparison of the incidence of serious adverse events (SAEs), selected
    adverse events (see Section 3.3.3), and adverse events (AEs) leading to
    study treatment discontinuation
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet the following criteria to be eligible for study entry:
    • Signed Informed Consent Form
    • ≥ 18 years of age
    • Histologically confirmed carcinoma of the breast with measurable or
    non-measurable metastatic disease that has progressed Patients with a history of brain metastasis are eligible for study participation (U.S. only), as long as their brain metastases have been treated and they have no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT scans) during the screening period. CT scan with contrast or MRI scan of the brain must be performed at least 3 weeks after completion of all therapy to the brain.
    Treatment for brain metastasis may include the following: WBRT, SRS
    (Gamma knife, LINAC, or equivalent), or a combination as deemed appropriate by
    the treating physician. Radiotherapy and stereotactic radiosurgery must be
    completed at least 4 weeks prior to Day 0.
    Patients may also have neurosurgical resection. Neurosurgery must be completed
    at least 6 weeks prior to Day 0, and brain biopsy must be completed at least
    4 weeks prior to Day 0.

    • Progression of disease during or following administration of one
    (non-investigational) chemotherapy regimen, defined as single-agent
    chemotherapy administered prior to or during disease progression or a
    pre-specified combination or sequence of cytotoxic agents administered in the
    first-line setting

    Subjects whose initial treatment changed prior to progression in the
    first-line setting are ineligible unless the change occurred within 30 days
    of initial treatment due to toxicity.
    • ECOG performance status of 0 or 1 (see Appendix B)
    • For women of childbearing potential, use of an effective means of
    non-hormonal contraception
    • Life expectancy ≥ 3 months
    • Willingness and capacity to comply with study and follow-up proceduresfirst-line setting are ineligible unless the change occurred within 30 days
    of initial treatment due to toxicity.
    • ECOG performance status of 0 or 1 (see Appendix B)
    • For women of childbearing potential, use of an effective means of
    non-hormonal contraception
    • Life expectancy ≥ 3 months
    • Willingness and capacity to comply with study and follow-up procedures
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria will be excluded from study entry:
    a. Disease Treatment History
    • Prior hormonal therapy only as treatment for metastatic disease
    without chemotherapy. Patients must have received chemotherapy for their
    metastatic disease in the first-line setting. Hormone therapy alone is not allowed.
    • For subjects who have received prior anthracycline-based therapy,
    documentation of left ventricular ejection fraction < 50% by either
    multiple gated acquisition (MUGA) or echocardiogram (ECHO)
    • Treatment with more than one prior cytotoxic regimen for MBC
    • HER2-positive status
    In general, HER2-positive status will be identified by a fluorescence in situ
    hybridization (FISH) assay as evaluated at the institution or, if FISH is
    unavailable, a 2 + or 3 + immunohistochemistry result (but the method of
    identification may vary by region or institution). Patients who have unknown
    HER2 status, and for whom determination of HER2 status is not possible,
    are eligible for this study.
    • Unknown ER and PR status
    • Radiation therapy other than for palliation or brain metastasis, biologic therapy,
    or chemotherapy for MBC within 21 days prior to Day 0
    • Prior therapy with bevacizumab or other VEGF pathway–targeted therapy
    b. Bevacizumab Exclusion Criteria
    • Untreated brain metastasis
    • Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg on anti-hypertensive medications
    • Unstable angina
    • New York Heart Association Grade II or greater CHF (see Appendix C)
    • History of myocardial infarction within 6 months prior to Day 0 (the day of the
    first bevacizumab/placebo infusion)
    • History of stroke or transient ischemic attack within 6 months prior to Day 0
    • Clinically significant peripheral vascular disease
    • Evidence of bleeding diathesis or coagulopathy
    • Major surgical procedure, open biopsy, or significant traumatic injury within
    28 days prior to Day 0; anticipation of need for major elective surgical
    procedure during the study
    • Minor surgical procedures, fine-needle aspirations, or core biopsies within
    7 days prior to Day 0
    • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
    abscess within 6 months prior to Day 0
    • Serious, non-healing wound, ulcer, or bone fracture
    Subjects with fractures secondary to metastatic disease are eligible after
    appropriate radiotherapy.
    • History of anaphylactic reaction to monoclonal antibody therapy not controlled with
    treatment premedication
    c. General Exclusion Criteria
    • Inadequate organ function, as evidenced by any of the following laboratory
    values:
    Absolute neutrophil count < 1500/µL
    Platelet count < 100,000/µL
    Total bilirubin > 1.5 mg/dL
    AST and/or ALT > 2 × the upper limit of normal (ULN) ( > 5 × the ULN in
    subjects with known liver involvement)
    Alkaline phosphatase >2 × the ULN (>7 × the ULN in subjects with known
    bone involvement)
    Serum creatinine > 2.0 mg/dL
    International normalized ratio (INR) > 1.5 × and/or activated partial
    thromboplastin time > 1.5 × the ULN (except for subjects receiving
    anti-coagulation therapy)
    Urine protein to creatinine ratio > 1.0 at screening for U.S. subjects
    (see Appendix F) or urine dipstick for proteinuria ≥ 1+ at screening followed by
    24-hour urine collection demonstrating > 1 g protein/24 hours for ROW subjects
    • History of other malignancies within 5 years of Day 0, except for tumors with
    a negligible risk for metastasis or death, such as adequately controlled
    basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of
    the cervix
    Subjects with a history of bilateral breast cancer or history of breast cancer will be
    eligible.
    • Pregnancy (positive serum pregnancy test) or lactation
    • Any other diseases, metabolic dysfunction, physical examination finding,
    or clinical laboratory finding giving reasonable suspicion of a disease or
    condition that contraindicates the use of an investigational drug or that may
    affect the interpretation of the results or renders the subject at high risk from
    treatment complications
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint: Progression-Free Survival
    Disease progression will be assessed by the investigator according to RECIST
    (see Appendix G). PFS is defined as the time from randomization to disease
    progression or death during second-line therapy due to any cause, whichever occurs
    first. Death during second-line therapy is defined as death within 30 days of the last dose of chemotherapy or study drug during second-line therapy. Data for subjects without disease progression or death during second-line therapy will be censored at the time of the last tumor assessment during second-line therapy (or, if no tumor assessments were performed after the baseline visit, at the time of randomization plus 1 day). Data for subjects who received third-line therapy without having documented disease progression and who did not die
    within 30 days of their last dose of chemotherapy or study drug during second-line therapy will also be censored at the time of the last tumor assessment during second-line therapy.
    PFS will be formally tested using a two-sided stratified log-rank test. The
    stratification factors are chemotherapy chosen on study (taxane, gemcitabine,
    vinorelbine, capecitabine), ER and PR status (ER and PR negative, other), and interval
    from initial metastatic disease diagnosis to progression after first-line cytotoxic
    chemotherapy (< 6 months, ≥ 6 months). Results from an unstratified log-rank test
    will also be presented. Kaplan-Meier methodology will be used to estimate median
    PFS for each treatment arm, and the Kaplan-Meier curve will be constructed to
    provide a visual depiction of the difference between the treatment arms.
    A two-step, hierarchical primary analysis of PFS will be conducted at the final
    analysis on subjects who receive non-capecitabine therapy (taxane, gemcitabine, or
    vinorelbine) and subjects who receive any protocol-allowed chemotherapy. Step 1
    will assess efficacy in subjects receiving non-capecitabine chemotherapy (taxane,
    gemcitabine, vinorelbine). Step 2 will assess efficacy in a pooled analysis of data from
    subjects who receive any protocol-allowed chemotherapy. If efficacy is demonstrated at the first step, analysis will proceed to the second step. However, if the first step does not demonstrate efficacy, analysis will not proceed to the second step. Details of the testing procedure will be provided in the Statistical Analysis Plan
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Yes
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned16
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA92
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2010-03-04. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 185
    F.4.2.2In the whole clinical trial 386
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-06-08
    P. End of Trial
    P.End of Trial StatusCompleted
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