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    Summary
    EudraCT Number:2014-003860-19
    Sponsor's Protocol Code Number:PM0259CA233B0
    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:2015-10-15
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-003860-19
    A.3Full title of the trial
    Randomised Phase II Study comparing, as first-line chemotherapy, single-agent Oral Vinorelbine administered with two different schedules in patients with Advanced Breast Cancer.
    Estudio fase II, aleatorizado, que compara, en primera línea de quimioterapia, vinorelbina oral, como agente único, en dos pautas de administración diferentes en pacientes con cáncer de mama avanzado.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study comparing oral Vinorelbine administered with two different schedules in patients with Advanced Breast Cancer.
    Estudio que compara la administración de vinorelbina oral de dos formas diferentes a pacientes con cáncer de mama avanzado.
    A.3.2Name or abbreviated title of the trial where available
    TEMPOBREAST-1
    A.4.1Sponsor's protocol code numberPM0259CA233B0
    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 SponsorPIERRE FABRE MEDICAMENT
    B.1.3.4CountryFrance
    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 supportPierre Fabre Medicament
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPIERRE FABRE IBÉRICA, S.A.
    B.5.2Functional name of contact pointInformación sobre Ensayos Clínicos
    B.5.3 Address:
    B.5.3.1Street AddressBlue Building - Marina Village
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08.005
    B.5.3.4CountrySpain
    B.5.4Telephone number+3493483 30 49
    B.5.6E-mailgustavo.villanova@pierre-fabre.com
    D. IMP Identification
    D.IMP: 1
    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.2.1.1.1Trade name Navelbine 20mg soft capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPierre fabre Medicament
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 Capsule, soft
    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 INNVINORELBINE TARTRATE
    D.3.9.1CAS number 125317-39-7
    D.3.9.2Current sponsor codePM0259
    D.3.9.4EV Substance CodeSUB20777
    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: 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.2.1.1.1Trade name Navelbine 30mg soft capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Medicament
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 Capsule, soft
    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 INNVINORELBINE TARTRATE
    D.3.9.1CAS number 125317-39-7
    D.3.9.2Current sponsor codePM0259
    D.3.9.4EV Substance CodeSUB20777
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 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 Yes
    D.2.1.1.1Trade name Navelbine 20mg soft capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Medicament
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 Capsule, soft
    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 INNVINORELBINE TARTRATE
    D.3.9.1CAS number 125317-39-7
    D.3.9.2Current sponsor codePM0259
    D.3.9.4EV Substance CodeSUB20777
    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: 4
    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 Navelbine 30mg soft capsules
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Medicament
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 Capsule, soft
    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 INNVINORELBINE TARTRATE
    D.3.9.1CAS number 125317-39-7
    D.3.9.2Current sponsor codePM0259
    D.3.9.4EV Substance CodeSUB20777
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.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
    Advanced Breast Cancer
    Cáncer de mama avanzado
    E.1.1.1Medical condition in easily understood language
    Breast Cancer
    Cáncer 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 18.1
    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 evaluate the Disease Control Rate (CR + PR + SD in both arms) assessed during study treatments.
    Evaluar la tasa de control de la enfermedad (RC + RP + EE en ambos brazos) durante los tratamientos del estudio.
    E.2.2Secondary objectives of the trial
    In both arms:
    -To evaluate the Duration of Disease Control
    -To evaluate the Disease Control Rate without grade 3-4 toxicity
    -To evaluate the Disease Control Rate without grade 3-4 neutropenia
    -To evaluate the Objective Response Rate
    -To evaluate the Objective Response without grade 3-4 toxicity
    -To evaluate the Objective Response without grade 3-4 neutropenia
    -To evaluate the Duration of Response
    -To evaluate the Time to First Response
    -To evaluate the Duration of Stable Disease
    -To estimate the Progression-Free Survival
    -To estimate the Progression-Free Survival without grade 3-4 toxicity
    -To estimate the Progression-Free Survival without grade 3-4 neutropenia
    -To estimate the Time To Treatment Failure
    -To estimate the Overall Survival
    -To estimate the Tolerance
    -To estimate the Quality of Life.
    En ambos brazos:
    - Evaluar la duración del control de la enfermedad
    - Evaluar la tasa de control de la enfermedad sin toxicidad de grado 3-4
    - Evaluar la tasa de control de la enfermedad sin neutropenia de grado 3-4
    - Evaluar la tasa de respuestas objetivas
    - Evaluar las respuestas objetivas sin toxicidad de grado 3-4
    - Evaluar las respuestas objetivas sin neutropenia de grado 3-4
    - Evaluar la duración de la respuesta
    - Evaluar el tiempo hasta la primera respuesta
    - Evaluar la duración de la enfermedad estable
    - Estimar la supervivencia libre de progresión
    - Estimar la supervivencia libre progresión sin toxicidad de grado 3-4
    - Estimar la supervivencia libre de progresión sin neutropenia de grado 3-4
    - Estimar el tiempo hasta el fracaso del tratamiento
    - Estimar la supervivencia global
    - Estimar la tolerancia
    - Estimar la calidad de vida.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Patients must give written (personally signed and dated) informed consent before completing any study-related procedure;
    -Absence of psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; these conditions should be assessed with the patient before randomisation in the trial;
    -The patient must have access to social insurance if applicable according to the local regulations;
    -Patients > or = 18 years;
    -Histologically confirmed adenocarcinoma of the breast;
    -Karnofsky Performance status (KPS) > or = 70%;
    -Documented locally advanced or metastatic disease previously untreated by chemotherapy and not amenable to curative surgery or radiotherapy;
    -Hormone receptor positive disease determined by > or =1% positive stained cells for estrogen and/or progesterone receptor by immunohistochemistry on the primary tumor or on metastatic site;
    -HER2 negative (assessed by 0-1+ IHC or 2+ IHC with FISH or CISH negative) on the primary tumor or on metastatic site;
    -Patients should have progressed to at least one previous hormone therapy for breast cancer at any stage of the disease and/or should be considered as no longer candidates to further hormone therapy;
    -Patients who have received adjuvant or neoadjuvant chemotherapy are allowed if the interval between the end of chemotherapy and the date of registration in the trial is superior to 12 months;
    -Complete staging within 4 weeks prior to randomisation;
    -Presence of at least one measurable lesion which has not been previously irradiated (RECIST criteria. Version 1.1). Measurable lesions (measured in at least one dimension, longest diameter to be recorded) as > or = 20 mm with conventional techniques or as > or = 10 mm with CT scan. Physical examination and ultrasound will not be considered as objective tumour assessments;
    -Women of childbearing potential must be using a medically accepted method of contraception to avoid pregnancy during the 2 months preceding the start of study treatment, throughout the study period and for up to 3 months after the last dose of study treatment in such a manner that the risk of pregnancy is minimised;
    -Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study treatment;
    -Fertile men must be using an effective method of birth control if their partners are women of childbearing potential throughout the study period and for up to 3 months after the last dose of study treatment;
    -Patients may have received prior radiotherapy but a minimum of a 4 weeks interval must have elapsed;
    -Life expectancy > or = 16 weeks;
    -Adequate bone marrow, hepatic and renal functions as evidenced by the following:
    -Haemoglobin > or = 10 g/dL
    -Absolute Neutrophil Count > or = 1.5 x 109/L
    -Platelet Count > or = 100 x 10^9/L
    -Total Bilirubin < 1.5 x ULN (ULN: Upper Limit of Normal)
    -SGOT/SGPT < or = 2.5 x ULN
    -Alkaline phosphatase < 5 x ULN
    -Creatinine Clearance > 40 mL/min, calculated using the Cockroft and Gault formula.
    - Los pacientes deberán otorgar su consentimiento informado por escrito (firmado y fechado personalmente) antes de llevar a cabo cualquier procedimiento relacionado con el estudio;
    - Ausencia de características psicológicas, familiares, sociológicas o geográficas que puedan dificultar el cumplimiento del protocolo y el seguimiento del estudio; estas características deberán evaluarse con el paciente antes de su aleatorización en el estudio;
    - Pacientes de 18 años o mayores;
    - Adenocarcinoma de mama confirmado histológicamente;
    - Estado funcional de Karnofsky (EFK) = o > 70%;
    - Enfermedad localmente avanzada o metastásica documentada, no tratada previamente con quimioterapia, ni susceptible de cirugía o radioterapia con intención curativa;
    - Enfermedad con receptores hormonales positivos, determinada mediante 1% de células con tinción inmunohistoquímica (IHQ) positiva para el receptor estrogénico y/o de la progesterona en el tumor primario o en alguna localización metastásica;
    - Estado de HER2 negativo (evaluado mediante IHQ 0-1+ o IHQ 2+ con FISH o CISH negativo) en el tumor primario o en alguna localización metastásica;
    - Los pacientes deberán haber progresado al menos a una hormonoterapia previa para el cáncer de mama en cualquier estadío de la enfermedad y/o no considerarse ya candidatos para recibir terapia hormonal adicional;
    - Los pacientes que hayan recibido quimioterapia adyuvante o neoadyuvante podrán participar en el estudio si el intervalo entre el final de la quimioterapia y la fecha de registro en el ensayo es superior a 12 meses;
    - Completar el estudio de extensión de la enfermedad del paciente dentro de las 4 semanas previas a la aleatorización;
    - Presencia de como mínimo una lesión medible que no haya sido irradiada previamente (criterios RECIST. Versión 1.1). Lesiones medibles (medidas en una dimensión como mínimo, debiéndose registrar su diámetro mayor): de = o > 20 mm con técnicas convencionales o = o > 10 mm con TAC. La exploración física y la ecografía no se considerarán evaluaciones objetivas del tumor;
    - Las mujeres en edad fértil deberán utilizar un método anticonceptivo médicamente aceptado para evitar el embarazo durante los 2 meses previos al inicio del tratamiento del estudio, durante la duración del período del estudio y durante los 3 meses posteriores a la última administración del tratamiento del estudio, de forma que se reduzca al mínimo el riesgo de embarazo;
    - Las mujeres en edad fértil deberán presentar un resultado negativo de la prueba de embarazo en suero u orina dentro de las 72 horas previas al inicio del tratamiento del estudio;
    - En caso de que sus parejas sean mujeres en edad fértil, los varones fértiles deberán utilizar un método anticonceptivo eficaz durante todo el período del estudio y hasta completar 3 meses después de la última dosis del tratamiento del estudio;
    - Los pacientes podrán haber recibido radioterapia previa, pero será necesario que haya transcurrido un intervalo mínimo de 4 semanas;
    - Esperanza de vida 16 semanas;
    - Función de la médula ósea, hepática y renal adecuadas, determinadas por los siguientes parámetros:
    - Hemoglobina 10 g/dl
    - Recuento absoluto de neutrófilos 1,5 x 109/l
    - Recuento de plaquetas 100 x 109/l
    - Bilirrubina total < 1,5 x LSN (LSN: Límite superior de normalidad)
    - SGOT/SGPT 2,5 x LSN
    - Fosfatasa alcalina < 5 x LSN
    -Aclaramiento de creatinina > 40 ml/min, calculado mediante la fórmula de Cockroft y Gault.
    E.4Principal exclusion criteria
    -Female is not eligible to enter the study if :
    -pregnant or lactating
    -with positive pregnancy test at inclusion;
    -Patients with symptoms suggesting CNS involvement or leptomeningeal metastases;
    -Concomitant hormonal therapy for advanced breast cancer;
    -Malabsorption syndrome or disease significantly affecting gastro-intestinal function or major resection of the stomach or proximal small bowel that could affect absorption of oral vinorelbine;
    -Prior treatment with chemotherapy in the locally advanced or metastatic setting;
    -Patients with dysphagia, or inability to swallow the tablets;
    -Other serious illness or medical conditions:
    -Clinically significant cardiac disease
    -Unstable diabetes
    -Uncontrolled hypercalcemia
    -Clinically significant active infections (current or in the last two weeks)
    -Previous organ allograft;
    -Current peripheral neuropathy > or = grade 2 according to NCI version 4.0 criteria;
    -Participation in another clinical trial with any investigational drug within 30 days prior to randomisation and/or during the study;
    -History of another malignancy within the past five years except basal cell carcinoma of the skin or carcinoma in situ of the cervix;
    -Known hypersensitivity to vinca alkaloids.
    - Las mujeres no serán elegibles para ser incluidas en el estudio si :
    - están embarazadas o en período de lactancia
    - presentan un resultado positivo de la prueba de embarazo en el momento de la inclusión;
    - Pacientes con síntomas que sugieran afectación del SNC o metástasis leptomeníngeas;
    - Terapia hormonal concomitante para el cáncer de mama avanzado;
    - Síndrome de malabsorción o patologías que afecten de forma importante a la función gastrointestinal o resecciones extensas del estómago o de la porción proximal del intestino delgado que puedan afectar a la absorción de la vinorelbina oral;
    - Tratamiento previo con quimioterapia para la enfermedad localmente avanzada o metastásica;
    - Pacientes con disfagia o incapaces de tragar cápsulas;
    - Otras enfermedades o patologías médicas graves:
    - Cardiopatía clínicamente significativa
    - Diabetes inestable
    - Hipercalcemia no controlada
    - Infecciones activas clínicamente relevantes (actuales o durante las últimas 2 semanas)
    - Trasplante alogénico previo de un órgano;
    - Neuropatía periférica actual grado 2, según la versión 4.0 de los criterios del NCI;
    - Participación en otro ensayo clínico con cualquier fármaco en investigación dentro de los 30 días previos a la aleatorización y/o durante el estudio;
    - Antecedentes de otra neoplasia maligna dentro de los 5 años previos, a excepción del carcinoma cutáneo de células basales o el carcinoma in situ de cérvix;
    - Hipersensibilidad conocida a los alcaloides de la vinca.
    E.5 End points
    E.5.1Primary end point(s)
    Disease Control Rate (CR + PR + SD in both arms) assessed during study treatments in both arms
    Evaluar la tasa de control de la enfermedad (RC + RP + EE en ambos brazos) durante los tratamientos del estudio
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumour assessments will be performed according to the RECIST guidelines (version 1.1). Assessments will be carried out at baseline and every 6 weeks until disease progression.
    Las evaluaciones del tumor se llevarán a cabo según los criterios RECIST (versión 1.1). Se realizará una evaluación en la visita basal y posteriormente cada 6 semanas hasta la progresión de la enfermedad
    E.5.2Secondary end point(s)
    In both arms;
    -To evaluate the Duration of Disease Control
    -To evaluate the Disease Control Rate without grade 3-4 toxicity
    -To evaluate the Disease Control Rate without grade 3-4 neutropenia
    -To evaluate the Objective Response Rate
    -To evaluate the Objective Response without grade 3-4 toxicity
    -To evaluate the Objective Response without grade 3-4 neutropenia
    -To evaluate the Duration of Response
    -To evaluate the Time to First Response
    -To evaluate the Duration of Stable Disease
    -To estimate the Progression-Free Survival
    -To estimate the Progression-Free Survival without grade 3-4 toxicity
    -To estimate the Progression-Free Survival without grade 3-4 neutropenia
    -To estimate the Time To Treatment Failure
    -To estimate the Overall Survival
    -To estimate the Tolerance
    -To estimate the Quality of Life.
    En ambos brazos:
    - Evaluar la duración del control de la enfermedad
    - Evaluar la tasa de control de la enfermedad sin toxicidad de grado 3-4
    - Evaluar la tasa de control de la enfermedad sin neutropenia de grado 3-4
    - Evaluar la tasa de respuestas objetivas
    - Evaluar las respuestas objetivas sin toxicidad de grado 3-4
    - Evaluar las respuestas objetivas sin neutropenia de grado 3-4
    - Evaluar la duración de la respuesta
    - Evaluar el tiempo hasta la primera respuesta
    - Evaluar la duración de la enfermedad estable
    - Estimar la supervivencia libre de progresión
    - Estimar la supervivencia libre progresión sin toxicidad de grado 3-4
    - Estimar la supervivencia libre de progresión sin neutropenia de grado 3-4
    - Estimar el tiempo hasta el fracaso del tratamiento
    - Estimar la supervivencia global
    - Estimar la tolerancia
    - Estimar la calidad de vida.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumour assessments will be performed according to the RECIST guidelines (v 1.1). Assessments will be carried out at baseline and every 6 weeks until disease progression.
    Clinical safety will be assessed by:
    -complete history of malignant and non malignant disease
    -full physical examination including vital signs, weight, PS
    -regular reporting of AEs that will be graded by using NCI/CTC grading v 4.0.
    -complete blood cell counts on a weekly basis
    -serum chemistry at baseline then on day 1 of each cycle
    The EORTC QLQ-C30 V 3.0 quality of life questionnaires will be filled in at baseline before randomisation, then immediately before cycle 2, cycle 4, cycle 6 etc., and at the end of study treatment. Changes of the scores from baseline of the parameters will be provided from baseline.
    Las evaluaciones del tumor siguen los criterios RECIST (versión 1.1). Se hará una evaluación en la visita basal y cada 6 semanas hasta progresión de la enfermedad.
    La seguridad clínica se evaluará:
    - historia clínica completa de la patología maligna y no maligna.
    - exploración física completa, incluyendo constantes vitales, peso y estado funcional (EF)
    - notificación de los AEs, clasificados NCI/CTCAE versión 4.0.
    - hemograma completo, semanal.
    - bioquímica sérica en visita basal y el día 1 de cada ciclo.
    Cuestionarios de calidad de vida EORTC QLQ-C30 (V. 3.0) en visita basal antes de la aleatorización, luego antes de los ciclos 2, 4, 6 etc.… y al finalizar el tratamiento del estudio. Se proporcionarán los cambios en las puntuaciones de los parámetros desde la situación basal.
    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 Yes
    E.6.13.1Other scope of the trial description
    Quality of life
    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 Yes
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Same medicinal product with different posology
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Austria
    Czech Republic
    France
    Germany
    Hungary
    Italy
    Poland
    Portugal
    Romania
    Spain
    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
    The end of the study period is defined as the date of last progression observed in the study. The follow-up period is the time from 30 days after the last study treatment administration until death. Survival information will be collected approximately every 6 weeks until progression of the disease and then every 3 months until death or decision for study closure.
    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 months6
    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 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: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 96
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 160
    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)
    The patient should not participate to any other clinical trial within 30 days after last doses of study treatment.
    For patients who discontinued the study treatment before the occurrence of disease progression.Clinical and radiological assessments of all lesions until disease progression are documented every 6 weeks, in addition to survival information listed below, including date of disease progression. Survival information will be collected approximately every 3 months until death.
    El paciente no debe participar en ningún otro Estudio dentro de los 30 días siguientes a la última administración del tratamiento.
    Para los pacientes que suspendan el tratamiento antes de que se produzca la progresión de la enfermedad:cada 6 semanas se recogerán las evaluaciones clínicas y radiológicas de cada lesión hasta progresión de enfermedad, además se incluirá la fecha de progresión de enfermedad. Se recogerá la información de supervivencia aproximadamente cada 3 meses hasta el éxitus.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation GEICAM (Spanish Breast Cancer Research Group Foundation)
    G.4.3.4Network Country Spain
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-11-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-06
    P. End of Trial
    P.End of Trial StatusCompleted
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