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    Summary
    EudraCT Number:2013-005137-20
    Sponsor's Protocol Code Number:D0819C00003
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-02-25
    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 number2013-005137-20
    A.3Full title of the trial
    A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to assess the efficacy and safety of Olaparib Monotherapy versus Physician?s Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients with germline BRCA1/2 Mutations
    Estudio fase III, multicéntrico, abierto, aleatorizado, controlado, para evaluar la eficacia y la seguridad de olaparib en monoterapia frente a la quimioterapia de elección del médico en el tratamiento de pacientes con cáncer de mama metastásico con mutaciones germinales de BRCA1/2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.
    Valoración de la eficacia y la seguridad de olaparib en monoterapia frente a la quimioterapia de elección del médico en el tratamiento de pacientes con cáncer de mama metastásico con mutaciones germinales de BRCA1/2
    A.3.2Name or abbreviated title of the trial where available
    OlympiAD
    A.4.1Sponsor's protocol code numberD0819C00003
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02000622
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca Farmacéutica Spain, S.A.
    B.5.2Functional name of contact pointUnidad de Investigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressC/ Serrano Galvache, 56; Parque Norte, Edificio Roble
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28033
    B.5.3.4CountrySpain
    B.5.4Telephone number0034900200444
    B.5.6E-mailinformacionEECC-Spain@astrazeneca.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 nameOlaparib
    D.3.2Product code AZD2281
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNOLAPARIB
    D.3.9.1CAS number 763113-22-0
    D.3.9.3Other descriptive nameOLAPARIB
    D.3.9.4EV Substance CodeSUB32234
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 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.3.4Pharmaceutical form
    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 INNCAPECITABINE
    D.3.9.3Other descriptive nameCAPECITABINE
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2500
    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 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.3.4Pharmaceutical form
    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 INNVINORELBINE
    D.3.9.1CAS number 71486-22-1
    D.3.9.4EV Substance CodeSUB00069MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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.3.4Pharmaceutical form
    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 INNERIBULIN
    D.3.9.1CAS number 253128-41-5
    D.3.9.4EV Substance CodeSUB31134
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.4
    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 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 nameOlaparib
    D.3.2Product code AZD2281
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNOLAPARIB
    D.3.9.1CAS number 763113-22-0
    D.3.9.3Other descriptive nameOLAPARIB
    D.3.9.4EV Substance CodeSUB32234
    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.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic Breast Cancer
    Cancer de mama metástasico
    E.1.1.1Medical condition in easily understood language
    Breast Cancer
    Cancer de mama
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    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 determine the efficacy of single agent olaparib vs physician?s choice chemotherapy (capecitabine, vinorelbine or eribulin) by progression-free survival (PFS) using blinded independent central review (BICR) data assessed by Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
    Determinar la eficacia de olaparib como agente único frente a la quimioterapia de elección del médico (capecitabina, vinorelbina o eribulina) analizando la supervivencia libre de progresión (SLP) usando datos de revisión central independiente enmascarada (RCIE) evaluados mediante los Criterios de Evaluación de la Respuesta en Tumores Sólidos (RECIST 1.1).
    E.2.2Secondary objectives of the trial
    1.Efficacy of single agent olaparib vs physician's choice chemotherapy (capecitabine, vinorelbine or eribulin) by assessment of overall survival (OS).
    2.Efficacy of single agent olaparib vs physician's choice chemotherapy (capecitabine, vinorelbine or eribulin) by assessment of time to second progression, defined as objective radiological or symptomatic progression, or death (PFS2).
    3.Efficacy of single agent olaparib vs physician's choice chemotherapy (capecitabine, vinorelbine or eribulin) by assessment of objective response rate (ORR) using BICR data assessed by RECIST 1.1.
    4.Assessment of the effect of olaparib on the Health-related Quality of Life (HRQoL)measured by EORTC QLQ-C30 global QoL scale.
    5.Assessment of adverse events (AEs), graded by CTCAE (v4.0)
    6.Assessment of physical examination.
    7.Assessment of vital signs including blood pressure (BP), pulse and electrocardiogram (ECG).
    8.Assessment of laboratory parameters including clinical chemistry and haematology
    Eficacia de olaparib como agente único frente a la quimioterapia de elección del médico (capecitabina, vinorelbina o eribulina) analizando la supervivencia global. 2. la eficacia de olaparib como agente único frente a la quimioterapia de elección del médico (capecitabina, vinorelbina o eribulina) analizando el tiempo hasta la segunda progresión o muerte 3. Eficacia de olaparib como agente único frente a la quimioterapia de elección del médico (capecitabina, vinorelbina o eribulina) analizando la tasa de respuestas objetivas usando los datos de RCIE evaluados mediante RECIST 1.1. 4. Evaluar el efecto de olaparib sobre la calidad de vida relacionada con la salud (CdVRS) medida mediante la escala de CdV del QLQ-C30 de la EORTC. 5. Evaluar los efectos de los acontecimientos adversos, grado 4 de los CTCAE. 6. Avaluar el examen físico. 7. Evaluar constantes vitales incluyendo pulso,y electrocardiograma (ECG). 8 Evaluar parámetros de laboratorio incluyendo bioquimíca química y hematologia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. *Provision of informed consent prior to any study specific procedures
    2. *Patients must be male or female .18 years of age
    3. *Histologically or cytologically confirmed breast cancer with evidence of metastatic disease
    4. Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)
    5. *Patients must have received treatment with an anthracycline (e.g. doxorubicin, epirubicin) and a taxane (e.g. paclitaxel, docetaxel) in either an adjuvant or metastatic setting.
    6. *Patients who have received platinum (cisplatin or carboplatin, either as monotherapy or in combination) for advanced breast cancer are eligible to enter the study provided there has been no evidence of disease progression during the
    platinum chemotherapy
    7. Patients who have received platinum as potentially curative treatment for a prior cancer (e.g. ovarian cancer) or as adjuvant/neoadjuvant treatment for breast cancer are eligible provided at least 12 months have elapsed between the last dose of platinum-based treatment and randomisation.
    8. Patients with estrogen and/or progesterone receptor-positive disease must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy
    9. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT (MRI where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
    10. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
    . Haemoglobin . 10.0 g/dL with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days
    . Absolute neutrophil count (ANC) . 1.5 x 109/L
    . Platelet count . 100 x 109/L
    . Total bilirubin . 1.5 x institutional upper limit of normal
    . AST (SGOT)/ALT (SGPT) . 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be . 5x ULN
    . Serum creatinine . 1.5 x institutional upper limit of normal (ULN)
    11. *ECOG performance status 0-1 within 21 days of randomisation
    12. *Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test
    9. Postmenopausal is defined as:
    . Age > 60 yrs
    . Age < 60 and amenorrheic for 1 year or more in the absence of chemotherapy and/or hormonal treatment
    . LH, FSH and plasma oestradiol levels in the post menopausal range for women under 60 years of age
    . radiation-induced oophorectomy with last menses >1 year ago
    . or surgical sterilisation (bilateral oophorectomy or hysterectomy)
    13. *Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
    14. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary tumour if available For inclusion in
    a) the optional exploratory genetic research and/or
    b) the optional tumour biopsy research, patients must fulfil the following criteria:
    . Provision of informed consent for genetic research
    . Provision of informed consent for tumour biopsy research
    If a patient declines to participate in the optional exploratory genetic research or the optional tumour biopsy research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.
    1.Firma del consentimiento informado con anterioridad a la realización de cualquiera de los procedimientos específicos del ensayo
    2.Los pacientes deben ser varones o mujeres ?18 años
    3.Cáncer de mama confirmado histológicamente o citológicamente con evidencia de enfermedad metastásica
    4.Mutación documentada de BRCA1 o BRCA2 que se predice que es deletérea o se sospecha que es deletérea (se sabe o se predice que es perjudicial/conduce a pérdida de la función) 5.Los pacientes deben haber recibido tratamiento con una antraciclina (p. ej., doxorubicina, epirubicina) y un taxano (p. ej., paclitaxel, docetaxel) en el contexto adyuvante o metastásico.
    6.Los pacientes que han recibido platino (cisplatino o carboplatino, ya sea como monoterapia o en combinación) para el cáncer de mama avanzado son elegibles para entrar en el ensayo siempre que no haya habido evidencia de progresión de la enfermedad durante la quimioterapia con platino
    7.Los pacientes que han recibido platino como tratamiento potencialmente curativo para un cáncer previo (p. ej., cáncer de ovario) o como tratamiento adyuvante/neoadyuvante para el cáncer de mama son elegibles siempre que hayan pasado al menos 12 meses entre la última dosis de tratamiento basado en platino y la aleatorización.
    8.Los pacientes con enfermedad con receptores de estrógenos y/o progesterona positivos deben haber recibido y haber progresado al menos a un tratamiento hormonal (adyuvante o metastásico) o tener enfermedad que el médico responsable crea que es inadecuada para tratamiento hormonal
    9.Al menos una lesión (medible y/o no medible) que pueda evaluarse con exactitud en el momento basal mediante TC (RM cuando la TC esté contraindicada) y sea adecuada para evaluación repetida según los RECIST 1.1.
    10.Los pacientes deben tener una función normal de los órganos y de la médula ósea, medida dentro de los 28 días previos a la administración del tratamiento del ensayo, tal como se define a continuación:
    -Hemoglobina ? 10,0 g/dl sin transfusiones de sangre (concentrados de hematíes o transfusiones de plaquetas) en los últimos 28 días
    -Recuento absoluto de neutrófilos (RAN) ? 1,5 x 109/l
    -Recuento de plaquetas ? 100 x 109/l
    -Bilirrubina total ? 1,5 x límite superior de la normalidad del centro
    -AST (SGOT)/ALT (SGPT) ? 2,5 x límite superior de la normalidad del centro a menos que haya metástasis hepáticas, en cuyo caso deben ser ? 5x LSN
    -Creatinina sérica ? 1,5 x límite superior de la normalidad (LSN) del centro
    11.Estado funcional del ECOG 0-1 dentro de los 21 días previos a la aleatorización
    12.Posmenopáusicas o con evidencia de no estar embarazadas en mujeres potencialmente fértiles: prueba de embarazo negativa en orina o suero
    13.El estado posmenopáusico se define como uno de los siguientes:
    -Edad > 60 años
    -Edad < 60 y amenorreica durante 1 año o más en ausencia de quimioterapia y/o tratamiento hormonal
    -Niveles de LH, FSH y estradiol en el plasma en el rango posmenopáusico en mujeres menores de 60 años
    -Ooforectomía inducida por radiación con últimas menstruaciones hace > 1 año
    -o esterilización quirúrgica (ooforectomía bilateral o histerectomía).
    14.El paciente está dispuesto y es capaz de cumplir el protocolo durante todo el ensayo, incluido el someterse al tratamiento y las visitas y exploraciones programadas
    15.Muestra de tumor fijado en formol, incluido en parafina (FFIP), del tumor primario si está disponible
    Para inclusión en
    a)La investigación genética exploratoria opcional y/o
    b)La investigación opcional de biopsia tumoral,
    Los pacientes deben cumplir los criterios siguientes:
    -Aportación del consentimiento informado para investigación genética
    -Proporcionar el consentimiento informado para la investigación de la biopsia tumoral
    E.4Principal exclusion criteria
    1.*Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff/BCA staff and/or staff at the study site).
    2. BRCA1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., ?Variants of uncertain clinical significance? or ?Variant of unknown significance? or ?Variant, favour polymorphism? or ?benign polymorphism? etc.).
    3. Cytotoxic chemotherapy or non-hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Endocrine therapy must have been discontinued 7 or more days before Cycle 1 Day 1. Palliative radiotherapy must have been completed 14 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 2 weeks prior to study treatment.
    4. *Patients with HER2-positive disease (3+ by IHC or ISH amplified > 2.0).
    5. *Previous randomisation in the present study.
    6. Exposure to an investigational product within 30 days or 5 half lives (whichever is longer) prior to randomisation
    7. *Any previous treatment with a PARP inhibitor, including olaparib.
    8. *Patients with second primary cancer, EXCEPTIONS: adequately treated nonmelanoma skin cancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid
    tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for . 5 years prior to study entry.
    9. Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc >470 msec, patient will be eligible only if repeat ECG demonstrates QTc .470
    msec.
    10. *Patients cannot have received more than 2 prior lines of cytotoxic chemotherapy for metastatic disease. Prior treatments with hormonal therapy and non-hormonal targeted therapy are allowed and not counted as a prior line of cytotoxic chemotherapy. For the purposes of this protocol, the combination of an aromatase inhibitor and everolimus is not considered cytotoxic chemotherapy.
    *Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
    12. Persistent toxicities (.CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
    13. *Patients with myelodysplastic syndrome/treatment related acute myeloid leukaemia.
    14. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
    15. *Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
    16. *Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive bilateral lung disease on High Resolution Computed Tomography scan or any psychiatric disorder that would limit ability to comply with study procedures, and any other medical condition that, in the opinion of the investigator, places the patient at unacceptable risk of toxicity.
    17. *Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: Disease outside the CNS is present. No clinical evidence of progression since completion of CNS-directed therapy. Minimum of 2
    weeks between completion of radiotherapy and cycle 1 Day 1 and recovery from significant (Grade .3) acute toxicity with no ongoing requirement for . 10mg of prednisone per day or an equivalent dose of other corticosteroid.
    18. *Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
    19. Pregnant or breast feeding women.
    20. *Previous allogeneic bone marrow transplant.
    21. *Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
    22. *Whole blood transfusions in the last 120 days prior to enrolment to the study which may interfere with gBRCA testing (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no.10)
    1.Participación en la planificación y/o la realización del ensayo (aplica a personal de AstraZeneca/BCA y/o del centro del ensayo). 2.Mutaciones BRCA1 y/o BRCA2 que se consideran no deletéreas (p.ej.,?Variantes de significación clínica incierta?o?Variante de significación desconocida?o?Variante, a favor del polimorfismo?o?polimorfismo benigno?, etc.). 3.No se permite quimioterapia citotóxica o tto. dirigido no hormonal dentro de los 21 días previos al día 1 del ciclo 1. El tto. hormonal debe haberse suspendido 7 o más días antes del día 1 ciclo 1. La radioterapia paliativa debe haberse terminado 14 días o más antes del día 1 ciclo 1. El paciente puede recibir una dosis estable de bisfosfonatos o denosumab para metástasis óseas, antes y durante el ensayo, siempre que se haya comenzado el tto. al menos 5 días antes del tto. del ensayo. 4.Pacientes con enfermedad HER2-positiva (3+ mediante IHQ o ISH amplificada ? 2,0). 5.Pacientes aleatorizados previamente en el presente ensayo. 6.Exposición a un producto en investigación dentro de los 30 días o 5 semividas (lo que sea más largo) antes de la aleatorización. 7.Cualquier tto. previo con un inhibidor de PARP, incluido olaparib. 8.Pacientes con un segundo cáncer primario, EXCEPCIONES: cáncer cutáneo no- melanoma tratado adecuadamente, cáncer de cérvix in situ tratado de forma curativa, carcinoma ductal in situ (CDIS), carcinoma endometrial en estadio 1, grado 1 u otros tumores sólidos, incluidos los linfomas (sin afectación de la médula ósea) tratados de forma curativa, sin pruebas de enfermedad durante ? 5 años antes de su inclusión en este ensayo. 9.ECG en reposo con QTc > 470 ms detectado en 2 o más momentos dentro de un periodo de 24 h o antecedentes familiares de síndrome de QT largo. Si el ECG demuestra QTc > 470 ms, el paciente será elegible sólo si la repetición del ECG demuestra QTc ? 470 ms. 10.Los pacientes no pueden haber recibido más de 2 líneas previas de quimioterapia citotóxica para enfermedad metastásica. Se permiten ttos. previos con terapia hormonal y terapia dirigida no hormonal y no se cuentan como una línea previa de quimioterapia citotóxica. A efectos de este protocolo, la combinación de un inhibidor de la aromatasa y everolimus no se considera quimioterapia citotóxica. 11.Uso simultáneo de inhibidores potentes conocidos de CYP3A4 como ketoconazol, itraconazol, ritonavir, indinavir, saquinavir, telitromicina, claritromicina y nelfinavir. Para más detalles, consúltese el Apéndice I. 12.Toxicidades persistentes (grado ? 2 de los CTCAE) causadas por tratamiento previo para el cáncer, excluyendo alopecia y neuropatía periférica de grado 2 de los CTCAE. 13.Pacientes con síndrome mielodisplásico/leucemia mieloide aguda relacionada con el tratamiento. 14.Cirugía mayor dentro de las 2 semanas antes de comenzar el tratamiento del ensayo y los pacientes se deben haber recuperado de cualquier efecto de cualquier cirugía mayor. 15.Pacientes con inmunodepresión, p. ej., pacientes con seropositividad conocida al virus de la inmunodeficiencia humana (VIH).
    16.Pacientes consideradas de alto riesgo médico debido a un trastorno médico grave, no controlado, enfermedad sistémica no maligna o infección activa, no controlada. Los ejemplos incluyen, entre otras cosas, arritmia ventricular no controlada, infarto de miocardio reciente (dentro de los últimos 3 meses), trastorno convulsivo mayor no controlado, compresión inestable de la médula espinal, síndrome de vena cava superior, enfermedad pulmonar bilateral extensa en estudio de tomografía computadorizada de alta resolución o cualquier trastorno psiquiátrico que limitaría la capacidad de cumplir los procedimientos del ensayo y cualquier otro problema médico que, en opinión del investigador, coloque al paciente en un riesgo inaceptable de toxicidad. 17.Los pacientes con antecedentes de metástasis en el SNC tratadas son elegibles, siempre que cumplan todos los criterios siguientes: hay enfermedad fuera del SNC. No hay evidencia clínica de progresión desde la finalización de la terapia dirigida al SNC. Mínimo de 2 semanas entre la finalización de la radioterapia y el día 1 del ciclo 1 y recuperación de cualquier toxicidad aguda significativa (Grado ? 3) sin necesidad continuada de ? 10 mg de prednisona al día o una dosis equivalente de otros corticosteroides. 18.Pacientes incapaces de tragar la medicación administrada por vía oral y pacientes con trastornos gastrointestinales que probablemente interfieran con la absorción de la medicación del ensayo. 19.Mujeres embarazadas o en la lactancia. 20.Trasplante alogénico de médula ósea previo. 21.Pacientes con hipersensibilidad conocida a olaparib o a cualquiera de los excipientes del producto. 22.Transfusiones de sangre entera en los últ. 120 días antes del reclut. en el ensayo que puedan interferir con las pruebas de gBRCA (son aceptables las transfusiones de concentrados de hematíes y de plaquetas, para los periodos de tiempo, véase criterio de inclusión n.º10)
    E.5 End points
    E.5.1Primary end point(s)
    Progression Free Survival
    Supervivencia libre de Progresion
    E.5.1.1Timepoint(s) of evaluation of this end point
    Assessed when approx 75% patients have experienced objective disease progression by RECIST. RECIST assessments performed at baseline, every 6 wks for the first 6 mths, then every 12 wks until progression. Data collection will last up to approx 7 years
    Se valora cuando aproximadamente un 75 % de los pacientes hayan experimentado progresión de la enfermedad por RECIST. Se realizaran evaluaciones RECIST en el momento basal, cada 6 semanas los primeros 6 meses, despues cada 12 semanas hasta la progresion. La recogida de datos durará 7 años aproximadamente.
    E.5.2Secondary end point(s)
    1.Overall Survival
    2.Time from randomisation to second progression or death (PFS2).
    3.Objective Response Rate by BICR using RECIST 1.1
    4.Adjusted mean change from baseline in global QoL score from the EORTC-QLQ-C30 questionnaire.
    5.Safety and tolerability of olaparib by assessment of adverse events
    6.Safety and tolerability of olaparib by assessment of physical examination.
    7.Safety and tolerability of olaparib by assessment of vital signs.
    8.Safety and tolerability of olaparib by assessment of laboratory parameters.
    1. supervivencia global 2 -Tiempo desde la aleatorización a la segunda progresión, o muerte (SLP2) 3 Tasa de respuestas objetivas mediante RCIE usando los RECIST 1.1
    4 Variación media ajustada respecto al momento basal en la puntuación de CdV global del cuestionario QLQ-C30 de la EORTC
    5 Seguridad y tolerabilidad de olaparib por evaluaciones de acontecimientos adversos
    6 Seguridad y tolerabilidad de olaparib por evaluaciones de examen físico
    7 Seguridad y tolerabilidad de olaparib por evaluaciones de constantes vitales
    8 Seguridad y tolerabilidad de olaparib por evaluaciones parámetros de laboratorio
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.At PFS analysis & at approx 60% deaths, every 8 wks after objective progression. 2. At PFS analysis & final OS. After 1st objective progression, every 8 wks. 3. At time of PFS analysis. Baseline, every 6 wks for first 6 months, then every 12 wks until objective progression. 4. EORTC QLQ-C30 questionnaires to be completed at baseline & every 6 wks until disease progression. 5.AEs collected from informed consent until post treatment 30-day f/u period. 6. Baseline & until study treatment d/c & at the post treatment 30-day f/u visit. 7.Baseline & until study treatment d/c & at the post treatment 30-day f-u visit. 8.Baseline & until study treatment d/c & at the post treatment 30-day f-u visit.
    Study data collection for all endpoints is expected to last up to approximately 7 years.
    1 Análisis de SLP aproximadamente 60% de muertes cada 8 semanas despues del obj.de la progresión. 2 En el Analisis de la SG. Despues del primer obj cada 6 semanas los 1os 6 meses, entonces cada 12 semanas hasta el obj de progresión. los cuestionarios EORTC QLQ-C30 se completarán en el moment basal y cada 6 semanas hasta la progresión. 5 AA recogidos desde CI hasta visita de seguim. de 30 dias tras el tto .6 Momento basal y hasta discont/terminac del tto y en la vis. de seguimiento de 30 días tras tto. 7.Momento basal y hasta discontinuac/terminac. del tto y en vis. de seguimiento de 30 ds tras el tto. 8.Mom.basal y hasta la discontinuac/terminacion del tto y en vis.de seguim. de 30 ds tras el tto. La recogida de datos de todas las variables de valorac. se espera duren 7 años aprox
    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 No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 EEA44
    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
    Bulgaria
    China
    Czech Republic
    France
    Hungary
    Italy
    Japan
    Korea, Republic of
    Romania
    Russian Federation
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    LSLV
    Ultima visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 130
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 106
    F.4.2.2In the whole clinical trial 310
    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)
    Once patients have been discontinued from study treatment, other treatment options will be at the discretion of the investigator (Standard of Care).
    Una vez que los pacientes hayan sido retirados del tratamiento del ensayo, las opciones del tratamiento posteriores quedarán a criterio del investigador (Práctica Clínica Habitual)
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-22
    P. End of Trial
    P.End of Trial StatusOngoing
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