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    Summary
    EudraCT Number:2011-002913-12
    Sponsor's Protocol Code Number:M12-895
    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:2013-06-24
    Trial 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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2011-002913-12
    A.3Full title of the trial
    A Randomized, Phase 2 Study of the Efficacy and Tolerability of Veliparib in Combination with Temozolomide or Veliparib in Combination with Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Subjects with BRCA1 or BRCA2 Mutation and Metastatic Breast Cancer
    Estudio fase 2 aleatorizado para valorar la eficacia y tolerabilidad de veliparib en combinación con temozolomida o veliparib en combinación con carboplatino y pacitaxel, frente a placebo más carboplatino y paclitaxel, en pacientes con cáncer de mama metastásico con mutación de BRCA1 o BRCA2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of
    (a) Veliparib and Temozolomide or
    (b) Veliparib, Carboplatin and Paclitaxel or
    (c) Placebo, Carboplatin and Paclitaxel
    in patients with Breast Cancer
    Un estudio de:
    (a) Veliparib y Temozolomida o
    (b) Veliparib, Carboplatino y Paclitaxel o
    (c) Placebo, Carboplatino y Paclitaxel
    En pacientes con cancer de mama
    A.4.1Sponsor's protocol code numberM12-895
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAbbVie Deutschland GmbH & Co. KG
    B.1.3.4CountryGermany
    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 supportAbbVie Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAbbVie Ltd.
    B.5.2Functional name of contact pointEU Clinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressAbbott House, Vanwall Business Park, Vanwall
    B.5.3.2Town/ cityMaidenhead, Berkshire
    B.5.3.3Post codeSL6 4XE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 (0) 1628 644475
    B.5.5Fax number+44 (0) 1628 644330
    B.5.6E-maileu-clinical-trials@abbvie.com
    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 No
    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 nameVeliparib 10 mg
    D.3.2Product code ABT-888
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVeliparib
    D.3.9.2Current sponsor codeABT-888
    D.3.9.3Other descriptive name1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-pyrrolidinyl]-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    D.IMP: 2
    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 No
    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 nameVeliparib 20 mg
    D.3.2Product code ABT-888
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVeliparib
    D.3.9.2Current sponsor codeABT-888
    D.3.9.3Other descriptive name1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-pyrrolidinyl]-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    D.IMP: 3
    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 No
    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 nameVeliparib 40 mg
    D.3.2Product code ABT-888
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVeliparib
    D.3.9.2Current sponsor codeABT-888
    D.3.9.3Other descriptive name1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-pyrrolidinyl]-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 nameTemozolomide 5 mg
    D.3.2Product code TMZ
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTEMOZOLOMIDE
    D.3.9.1CAS number 85622-93-1
    D.3.9.3Other descriptive nameTMZ
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 nameTemozolomide 20 mg
    D.3.2Product code TMZ
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTEMOZOLOMIDE
    D.3.9.1CAS number 85622-93-1
    D.3.9.3Other descriptive nameTMZ
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 nameTemozolomide 100 mg
    D.3.2Product code TMZ
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTEMOZOLOMIDE
    D.3.9.1CAS number 85622-93-1
    D.3.9.3Other descriptive nameTMZ
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    D.IMP: 7
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 nameCarboplatin 10 mg/ml concentrate for solution for infusion
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNCARBOPLATIN
    D.3.9.1CAS number 41575-94-4
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    D.IMP: 8
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 namePaclitaxel
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 No
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    BRCA1 or BRCA2 mutation metastatic breast cancer
    Cáncer de mama metastásico con mutación de BRCA1 o BRCA2
    E.1.1.1Medical condition in easily understood language
    BRCA1 or BRCA2 mutation metastatic breast cancer
    Cáncer de mama metastásico con mutación de BRCA1 o BRCA2
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the progression-free survival of oral veliparib in combination with temozolomide or in combination with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 mutation and locally recurrent or metastatic breast cancer.
    Evaluar la supervivencia libre de progresión (SLP) de veliparib oral en combinación con temozolomida (TMZ) o en combinación con carboplatino y paclitaxel en comparación con placebo más carboplatino y paclitaxel en pacientes con mutación de los genes BRCA1 o BRCA2 y cáncer de mama localmente recurrente o metastásico.
    E.2.2Secondary objectives of the trial
    To assess overall survival, clinical benefit rate & objective response rate in those subjects treated with veliparib plus TMZ or treated with veliparib plus carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel.
    Evaluar la supervivencia global (SG), la tasa de beneficio clínico (TBC), la tasa de respuesta objetiva (TRO) en los pacientes tratados con veliparib en combinación con TMZ o tratados con veliparib más carboplatino y paclitaxel en comparación con placebo más carboplatino y paclitaxel
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. ? 18 years of age.
    2. Histologically or cytologically confirmed breast cancer that is either locally recurrent or metastatic. Locally recurrent disease must not be amenable to surgical resection or radiation with curative intent.
    3. Must have a documented deleterious BRCA1 or BRCA2 germline mutation. The investigator should ensure that the testing is consistent with local guidelines, and clinical practice, and that the
    test uses either 1) direct DNA sequencing/multiplex ligation-dependent probe amplification (MLPA) or 2) a well-characterized methodology previously validated by sequencing, such as that
    used to assess founder mutations. If testing has been performed by a laboratory other than Sponsor core laboratory, subjects may be enrolled but must be re-tested by Sponsor core laboratory for
    confirmation of BRCA1 or BRCA2 germline mutations.
    4. If HER2 positive (HER2 3+ by immunohistochemistry or amplification by fluorescence in situ hybridization [FISH > 2]), subjects must have received and progressed on at least one prior
    standard HER2-directed therapy or the subject must be ineligible to receive anti-HER2 therapy.
    5. Measurable or non-measurable (but radiologically evaluable disease per RECIST version 1.1 on computed tomography (CT) scan (within 28 days of C1D1) with at least one lesion outside previously irradiated areas.
    6. ECOG Performance status of 0 to 2 (within 28 days of C1D1).
    7. Adequate hematologic, renal, and hepatic function as detailed in the protocol.
    8. Women of childbearing potential and men must agree to use adequate contraception (one of the following listed below) prior to study entry, for the duration of study participation and for 90 days
    following completion of therapy. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation. To be considered of non-child bearing potential, postmenopausal women must be amenorrheic for at least 12 months or subjects must be surgically sterile.
    - Total abstinence from sexual intercourse (for a minimum of one complete menstrual cycle prior to study drug administration);
    - Vasectomized male subjects or vasectomized partner of female subjects;
    - Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream);
    - Intra-Uterine Device (IUD);
    - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 90 days following completion of therapy.
    9. Capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to initiation of any screening or study-specific procedures.
    1. Edad ? 18 años.
    2. Cáncer de mama confirmado mediante histología o citología localmente recurrente o metastásico. La enfermedad localmente recurrente no debe ser susceptible de resección quirúrgica o radioterapia con intención curativa.
    3. Deben tener una mutación de la línea germinal en los genes BRCA1 o BRCA2. El investigador debe asegurarse de que el análisis cumpla las normas locales y la práctica clínica y de que en él se utilice: 1) secuenciación directa de ADN (amplificación múltiple de sondas dependiente) de ligadura (MLPA, multiplex ligation-dependent probe amplification), o bien 2) una metodología bien caracterizada previamente validada mediante secuenciación, como la utilizada para evaluar mutaciones basales. Si el análisis ha sido realizado por un laboratorio distinto del laboratorio central del promotor, los pacientes podrán ser inscritos pero el laboratorio central del promotor deberá repetir el análisis para confirmar las mutaciones de la línea germinal de los genes BRCA1 o BRCA2.
    4. Si el análisis de HER2 es positivo (HER2 3+ mediante inmunohistoquímica o amplificación mediante hibridación in situ con fluorescencia [FISH > 2]), los pacientes deben haber recibido previamente al menos un tratamiento estándar dirigido al HER2 y haber experimentado progresión de la enfermedad durante dicho tratamiento o deben no ser aptos para recibir tratamiento anti-HER2.
    5. Enfermedad medible o no medible (pero radiológicamente evaluable) conforme a los criterios RECIST, versión 1.1, en la tomografía computarizada (TC) exploración (en los 28 días siguientes al D1C1) con al menos una lesión fuera de áreas previamente irradiadas.
    6. Estado funcional del ECOG de 0 a 2 (en los 28 días siguientes al D1C1).
    7. Adecuada función hematológica, renal y hepática tal y como se detalla en el protocolo.
    8. Las mujeres con capacidad de procrear y los hombres deberán comprometerse a utilizar un método anticonceptivo adecuado (uno de los mencionados a continuación) antes de incorporarse al estudio, durante la participación en el mismo y hasta 90 días después de finalizar el tratamiento. Las mujeres con capacidad de procrear deberán dar negativo en una prueba de embarazo en suero en los siete días previos al inicio. Para que se considere que no tienen capacidad de procrear, las mujeres posmenopáusicas deberán haber presentado amenorrea durante al menos 12 meses o deberán haber sido esterilizadas quirúrgicamente.
    - Abstinencia total de relaciones sexuales (como mínimo durante un ciclo menstrual completo antes de administración del fármaco del estudio);
    - Pacientes varones vasectomizados o parejas masculinas vasectomizadas de pacientes femeninas;
    - Método de doble barrera (preservativo, esponja anticonceptiva, diafragma o anillo vaginal con gel o crema espermicida);
    - Dispositivo intrauterino (DIU);
    - Además, los varones (incluidos los que han sido vasectomizados) cuyas parejas estén embarazadas o pudieran estar embarazadas deberán comprometerse a usar preservativo durante el estudio y durante 90 días después de la finalización del tratamiento.
    9. El paciente debe ser capaz de comprender y cumplir los parámetros explicados en el protocolo y de firmar y fechar el consentimiento informado aprobado por un Comité ético de investigación clínica antes del inicio de cualquier procedimiento de selección o específico del estudio.
    E.4Principal exclusion criteria
    1. Received anticancer agent(s) or an investigational agent within 21days prior to C1D1 or radiotherapy within 28 days prior to C1D1. Prior treatment with palliative local breast or bone lesion radiation (other than pelvis) can occur, if administered at least 14 days prior to C1D1. Subjects experiencing a significant adverse effect or toxicity (Grade 3 or Grade 4), causally attributed to previous anticancer treatment that has not recovered to at least Grade 2 are excluded. Anticancer hormonal therapy must be stopped 7 days before starting C1D1. Subjects receiving bisphosphonates or denosumab are eligible.
    2. More than 2 prior lines of cytotoxic chemotherapy (e.g., gemcitabine, doxorubicin, capecitabine) for metastatic disease.
    - Regimens received in the adjuvant/neoadjuvant setting or for locally recurrent breast cancer within the past 6 months will also be considered toward the maximum of 2 prior lines of therapy.
    - A regimen will be considered a line of therapy if it includes a cytotoxic agent administered for the treatment of breast cancer more than 1 full cycle. Therapy administered for 1 full cycle or less will not be counted towards the number of lines of therapy unless the patient experienced progression of disease while on that therapy.
    - Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) and signal transduction agents (e.g., trastuzumab lapatinib, erlotinib, gefitinib, bevacizumab) are allowed and are not counted towards the prior line of therapy.
    3. Prior treatment of breast cancer with temozolomide, a platinum agent, or a Poly-(ADP-ribose)-Polymerase (PARP)-inhibitor.
    - Therapy with temozolomide, a platinum agent, or a PARP inhibitor administered for 1 full cycle or less will not be considered as prior therapy unless the patient experienced progression of disease while on that therapy.
    4. Prior taxane therapy administered for the treatment of metastatic breast cancer disease with the below exceptions.
    - Prior taxane therapy for metastatic breast cancer is allowed if the patient received ? 1 full cycle (i.e., within 4 weeks for subjects receiving weekly paclitaxel or Abraxane; within 3 weeks for subjects receiving paclitaxel or docetaxel every 3 weeks) in the absence of progression or if taxane therapy for metastatic disease was > 12 months prior to C1D1.
    - Use of taxanes as adjuvant therapy or to treat locally recurrent disease is permitted, if given more than 6 months prior to C1D1.
    In all cases, the subject must be an appropriate candidate for paclitaxel therapy as per standard practice and per the investigator's discretion.
    5. A history of or evidence of brain metastases or leptomeningeal disease. Subjects with symptoms to suggest central nervous system (CNS) metastases should have a brain MRI within 28 days of enrollment to confirm the absence of CNS metastases. Contrast CT is acceptable for subjects who are unable to undergo a brain MRI.
    6. A history of uncontrolled seizure disorder.
    7. Pre-existing neuropathy from any cause in excess of Grade 1.
    8. Known history of allergic reactions to cremophor-paclitaxel.
    9. Clinically significant uncontrolled condition(s).
    - Active infection;
    - Symptomatic congestive heart failure;
    - Unstable angina pectoris or cardiac arrhythmia;
    - Myocardial infarction within last 6 months;
    - Psychiatric illness/social situations that would limit compliance with study requirements;
    or
    - Any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities.
    10. A previous or concurrent cancer that is distinct in primary site or histology from metastatic breast cancer, except cervical carcinoma in situ, non-melanoma carcinoma of the skin, or in situ
    carcinoma of the bladder. Any cancer curatively treated greater than 3 years prior to entry is permitted. For these subjects, metastases must be histologically or cytologically confirmed to be
    breast cancer.
    11. Pregnant or breastfeeding.
    1. Haber recibido fármacos antineoplásicos o un fármaco en investigación en los 21 días anteriores al D1C1 o radioterapia en los 28 días anteriores al D1C1. Pueden haber recibido tratamiento previo con radioterapia paliativa local de lesiones mamarias u óseas (excepto en la pelvis) si este se ha administrado al menos 14 días antes del D1C1. Se excluye a los pacientes que presenten un acontecimiento adverso importante (de grados 3 o 4) atribuido causalmente al tratamiento antineoplásico previo que no se haya recuperado hasta al menos un grado 2. La hormonoterapia antineoplásica deberá suspenderse 7 días antes de iniciar el D1C1. Podrán participar los pacientes que reciban bisfosfonatos o denosumab.
    2. Más de dos líneas previas de quimioterapia citotóxica (por ejemplo, gemcitabina, doxorubicina, capecitabina) para la enfermedad metastásica.
    - Los tratamientos recibidos en el contexto adyuvante/neoadyuvante o para el cáncer de mama localmente recurrente en los últimos seis meses también se considerarán dentro del máximo de dos líneas previas de tratamiento.
    - Un tratamiento se considerará una línea de tratamiento si incluye un fármaco citotóxico administrado durante más de un ciclo completo. El tratamiento administrado durante un ciclo completo o menos no se contabilizará para el número de líneas de tratamiento a menos que el paciente haya experimentado progresión de la enfermedad durante dicho tratamiento.
    - Se permiten los tratamientos anteriores hormonales (tamoxifeno, inhibidores de la aromatasa) y los tratamientos con agentes de transducción de señales (por ejemplo, trastuzumab, lapatinib, erlotinib, gefitinib, bevacizumab), que no se contabilizarán para determinar las líneas previas de tratamiento.
    3. Tratamiento previo del cáncer de mama con temozolomida, un fármaco con platino o inhibidor de poli-(ADP-ribosa)-polimerasa (PARP).
    - El tratamiento con temozolomida, un fármaco con platino o un inhibidor de PARP administrado durante un ciclo completo o menos no se considerará un tratamiento previo a menos que el paciente haya experimentado progresión de la enfermedad durante dicho tratamiento.
    4. Tratamiento previo con taxanos administrado para el cáncer de mama metastásico con las siguientes excepciones.
    - El tratamiento previo con taxanos para el cáncer de mama metastásico se permite si el paciente ha recibido ? 1 ciclo completo (es decir, en el plazo de 4 semanas para los pacientes tratados semanalmente con paclitaxel o Abraxane; en el plazo de 3 semanas para los pacientes tratados con paclitaxel o docetaxel cada 3 semanas) en ausencia de progresión o si el tratamiento con taxanos para la enfermedad metastásica se administró más 12 meses antes del D1C1.
    - El uso de taxanos como tratamiento adyuvante o para tratar la enfermedad localmente recurrente se permite siempre que se haya administrado más de 6 meses antes del D1C1.
    En todos los casos, el paciente deberá ser un candidato adecuado para el tratamiento con paclitaxel de acuerdo con la práctica habitual y con el criterio del investigador.
    5. Antecedentes o signos de metástasis cerebrales o enfermedad leptomeníngea. Los pacientes que presenten síntomas indicativos de metástasis del sistema nervioso central (SNC) deberán someterse a una RM cerebral en los 28 días previos a la inscripción para confirmar la ausencia de metástasis en el SNC. Se acepta un TC con contraste para los pacientes que no puedan someterse a una RM cerebral.
    6. Antecedentes de trastornos convulsivos no controlados.
    7. Neuropatía preexistente por cualquier causa de grado > 1.
    8. Antecedentes conocidos de reacciones alérgicas a Cremofor-paclitaxel.
    9. Trastornos con importacia clínica no controlados.
    - Infección activa;
    - Insuficiencia cardíaca copngestiva sintomática;
    - Angina de pecho inestable o arritmia cardíaca;
    - Infarto de miocardio en los últimos 6 meses;
    - Enfermedad psiquiátrica o situación social que limitaría el cumplimiento de los requisitos del estudio ;
    o
    - Cualquier proceso médico que, en opinión del investigador, suponga un riesgo inaceptablemente alto de reacciones adversas para el paciente.
    10. Un cáncer previo o concomitante que sea distinto del cáncer de mama metastásico en cuanto al foco primario o a las características histológicas, salvo el carcinoma cervicouterino in situ, el carcinoma de piel distinto del melanoma o el carcinoma in situ de la vejiga. Se permite cualquier cáncer tratado de forma curativa más de 3 años antes de la entrada en el estudio. Estos pacientes deben tener una confirmación histológica o citológica de que se trata de metástasis de cáncer de mama.
    11. Mujeres embarazadas o en periodo de lactancia.
    E.5 End points
    E.5.1Primary end point(s)
    Progression Free Survival
    Supervivencia Libre de Progresión
    E.5.1.1Timepoint(s) of evaluation of this end point
    Progression Free Survival is defined as the number of days from the date the subject was randomized to the date the subject experienced a confirmed event of disease progression (as determined by the central imaging center), or to the date of death (all causes of mortality), if disease progression is not reached.
    La Supervivencia Libre de Progresión se definirá como el número de días transcurridos desde la fecha de aleatorización del paciente hasta la fecha en que este experimente un acontecimiento de progresión de la enfermedad (confirmada por el centro de imágenes central) o hasta la fecha de la muerte (muerte por cualquier causa) si no se alcanza la progresión de la enfermedad.
    E.5.2Secondary end point(s)
    Overall Survival, Clinical Benefit Rate and Objective Response Rate
    Supervivencia global, Tasa de beneficio clínico y Tasa de respuesta objetiva
    E.5.2.1Timepoint(s) of evaluation of this end point
    Overall Survival - number of days from randomization to date of death.

    Clinical Benefit Rate - number of subjects who have at least stable disease or Non-CR/Non-PD through the end of Week 18. All intent to treat subjects will be included in the analysis.

    Objective Response Rate - all subjects who have had at least one measurable lesion at baseline will be included in the objective response rate calculation

    Chemotherapy-Induced Peripheral Neuropathy - scores from the EORTC QLQ-CIPN20 instrument will be evaluated per published literature. In addition, the incidence of treatment-emergent Grade 3 or 4 adverse events of peripheral neuropathy will be obtained.
    Supervivencia global,nº de días transcurridos desde el día de aleatorizacion hasta el de su muerte.Tasa de beneficio clínico,nº pacientes que presentan al menos Enfermedad Estable/ausencia de Respuesta Completa/ausencia de Progresión de Enfermedad hasta el fin de la semana 18.Se incluirán a todos los pacientes de la población por intención de tratar (IT).Tasa de respuesta objetiva:en el cálculo de esta Tasa se incluirá a todos los pacientes que hayan presentado al menos una lesión medible en el momento basal.Neuropatía periférica inducida por la quimioterapia,las puntuaciones obtenidas mediante el cuest QLQ-CIPN20 de la EORTC serán evaluadas conforme a bibliografía . Además,será obtenida la incidencia de acontecimientos adversos de neuropatía periférica de tratamiento emergente grado3o4.
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Parcialmente ciego
    Partially blinded
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Czech Republic
    Denmark
    Finland
    France
    Hungary
    Israel
    Norway
    Poland
    Russian Federation
    Slovakia
    Ukraine
    United States
    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
    The end-of-study is defined as the date of the last subject's last visit, or last follow-up visit, which is longer.
    Se define como fecha final del estudio la fecha de la última visita del último paciente, o la última visita de seguimiento, lo que ocurra más tarde.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 210
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 No
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 85
    F.4.2.2In the whole clinical trial 255
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Upon completion of the study, the subjects will be treated in accordance with the Investigator's best clinical judgement.
    Una vez completado el estudio, los pacientes serán tratados de acuerdo al mejor juicio clínico del Investigador.
    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 Decision2013-07-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-05
    P. End of Trial
    P.End of Trial StatusCompleted
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