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    Summary
    EudraCT Number:2016-003074-40
    Sponsor's Protocol Code Number:201973
    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:2017-01-04
    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 number2016-003074-40
    A.3Full title of the trial
    A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer.
    Estudio de fase I/II de aumento escalonado y expansión de la dosis para investigar la seguridad, la farmacocinética, la farmacodinámica y la actividad clínica de GSK525762 en combinación con fulvestrant en pacientes con cáncer de mama con receptores estrogénicos positivos (RE+)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study investigation GSK525762 in combination with fulvestrant in treatments of breast cancer.
    Estudio de investigación de GSK525762 en combinación con fulvestrant en pacientes con cáncer de mama
    A.4.1Sponsor's protocol code number201973
    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 SponsorGlaxoSmithKline Research & Development Limited
    B.1.3.4CountryUnited Kingdom
    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 supportGlaxoSmithKline Research & Development Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Limited
    B.5.2Functional name of contact pointGSK Clinical Support Help Desk
    B.5.3 Address:
    B.5.3.1Street Address1-3 Iron Bridge Road, Stockley Park West
    B.5.3.2Town/ cityUxbridge, Middlesex
    B.5.3.3Post codeUB11 1BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+448007839733
    B.5.6E-mailGSKClinicalSupportHD@gsk.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.3.2Product code GSK525762
    D.3.4Pharmaceutical form 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 INNto be determined
    D.3.9.2Current sponsor codeGSK525762
    D.3.9.3Other descriptive nameGSK525762
    D.3.9.4EV Substance CodeSUB122475
    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: 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.3.2Product code GSK525762
    D.3.4Pharmaceutical form 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 INNto be determined
    D.3.9.2Current sponsor codeGSK525762
    D.3.9.3Other descriptive nameGSK525762
    D.3.9.4EV Substance CodeSUB122475
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Faslodex
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFaslodex
    D.3.4Pharmaceutical form Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFulvestrant
    D.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    ER-positive Breast Cancer
    RE positivos Cáncer de mama
    E.1.1.1Medical condition in easily understood language
    Breast Cancer with growth promoted by estrogen - female hormone.
    Cáncer de mama con sobre expression de estrógenos- hormona femenina
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10070575
    E.1.2Term Estrogen receptor positive 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
    Phase I
    To determine a recommended Phase 2 dose of GSK525762, when given in combination with fulvestrant, in women with advanced or metastatic estrogen receptor positive breast cancer (ER+BC).

    Phase II
    To evaluate the effect of treatment with GSK525762 and fulvestrant, when given in combination, on progression-free survival in women with advanced or metastatic ER+BC.
    Fase I:
    Determinar una dosis recomendada de Fase 2 (DRF2) de GSK525762, cuando se suministre con fulvestrant, en mujeres con cáncer de mama de receptor de estrógeno positivo (CM+RE) en estado avanzado o metastásico.

    Fase II
    Evaluar la actividad clínica de GSK525762, cuando se suministre combinado con fulvestrant, en mujeres con CM+RE en estado avanzado o metastásico.
    E.2.2Secondary objectives of the trial
    -To determine the safety, tolerability, and maximum tolerated dose (MTD) of GSK525762, when given in combination with fulvestrant
    - To evaluate the clinical activity of GSK525762 and fulvestrant, when given in combination
    - To evaluate the effect of treatment with GSK525762 and fulvestrant, when given in combination on additional metrics of subject survival
    - To characterize the exposure to GSK525762 and fulvestrant, when given in combination
    - To characterize the exposure to GSK525762, when given in combination with fulvestrant
    - To characterize the exposure to fulvestrant when given alone or with GSK525762
    - To evaluate ESR1 mutational status as a potential indicator of sensitivity and/or response to GSK525762 and fulvestrant, when given in combination.
    - Determinar la seguridad, tolerabilidad y dosis máxima tolerada (DMT) de GSK525762, cuando se suministre combinado con fulvestrant .
    - Evaluar la actividad clínica de GSK525762 suministrado con fulvestrant .
    - Evaluar el efecto del tratamiento combinado de GSK525762 y fulvestrant en mujeres con CM+RE en estado avanzado o metastásico en mediciones adicionales de la supervivencia del sujeto.
    - Describir la exposición a GSK525762 y a fulvestrant cuando se dan en combinación.
    - Describir la exposición a GSK525762 suministrado con fulvestrant.
    - Describir la exposición a fulvestrant suministrado con o sin GSK525762.
    - Evaluar el estado mutacional de VSE1 como indicador potencial de sensibilidad y/o respuesta a GSK525762, cuando se suministre combinado con fulvestrant.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent provided
    2. Females 18 years old and greater (at the time of written consent)
    3. Histologically or cytologically confirmed diagnosis of advanced or metastatic adenocarcinoma of the breast.
    4. Documentation of ER-positive and/or PR-positive tumor based on local testing of the most recent tumor biopsy
    5. Documentation of HER2-negative tumor based on local testing of the most recent tumor biopsy
    6. History of prior therapy that satisfies one of the following criteria:
    a. AI failures: disease that progressed during treatment or within 12 months of completion of adjuvant therapy with tamoxifen and/or AI
    b.CDK 4/6 inhibitor plus letrozole failures: disease that progressed during treatment or within 1 month after the end of treatment with prior tamoxifen, AI, or the combination of a CDK4/6 inhibitor plus letrozole, for advanced/metastatic disease
    7. Any menopausal status
    8. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
    9. All prior treatment- related toxicities must be NCI-CTCAE v4 < Grade 1 (except alopecia (permitted at any grade) and peripheral neuropathy (permitted at < Grade 2) at the time of treatment allocation
    10. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1
    11. Adequate organ function
    12. Able to swallow and retain orally administered medication
    13. A female subject is eligible to participate if she is of:
    - non-childbearing potential
    - child-bearing potential and agrees to use one of the contraception methods
    - negative serum pregnancy test <7 days prior to first study drug dose - Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for at least 28 days following the last dose of study treatment.
    1. Consentimiento informado por escrito proporcionado
    2. Mujeres de 18 años o más (en el momento del consentimiento informado)
    3. Diagnóstico con confirmación citológica o histológica de adenocarcinoma de mama avanzado o metastásico
    4. Documentación de tumor RE positivo o RP positivo basada en análisis locales de la biopsia del tumor más reciente
    5. Documentación de tumor HER2 negativo basada en análisis locales de la biopsia del tumor más reciente
    6. Historial de tratamiento anterior que cumple uno de los siguientes criterios:
    a. Fallos de AA: la enfermedad ha avanzado durante el tratamiento o en un periodo de 12 meses tras finalizar el tratamiento adyuvante con tamoxifeno o AA
    b. Fallos del inhibidor CDK4/6 y letrozol: la enfermedad ha avanzado durante el tratamiento o en un periodo de 1 mes tras la finalización del tratamiento con tamoxifeno previo, AA, o la combinación de un inhibidor CDK4/6 y letrozol, para un estado metastásico o avanzado de la enfermedad
    7. Cualquier estado menopáusico
    8. Enfermedad cuantificable por los criterios 1.1 de Evaluación de Respuesta en Tumores Sólidos (RECIST)
    9. Cualquier toxicidad previa relacionada con el tratamiento debe ser NCI-CTCAE v4 < Grado 1 (excepto la alopecia [permitida en cualquier grado] y la neuropatía periférica [permitida en < Grado 2] en cualquier momento de la asignación al tratamiento
    10. Puntuación de 0 a 1 en la escala de valoración del Grupo Oncológico Cooperativo del Este (ECOG)
    11. Funcionamiento adecuado del órgano
    12. Capacidad de deglutir y retener la medicación administrada por vía oral
    13. Una mujer es apta para participar si:
    - no tiene posibilidad de quedarse embarazada.
    - tiene posibilidad de quedarse embarazada y acepta utilizar uno de los métodos anticonceptivos.
    - presenta una prueba de embarazo en suero negativa <7 días antes de la primera dosis del fármaco del estudio.
    Las mujeres lactantes deben dejar la lactancia antes de la primera dosis del tratamiento del estudio y deben evitarlo durante el periodo de tratamiento y como mínimo durante 28 días después de la última dosis del tratamiento del estudio.
    E.4Principal exclusion criteria
    1.Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of advanced/metastatic disease.
    2. Disease which has progressed despite prior fulvestrant therapy.
    3. ≥3 lines of systemic anti-cancer therapy (including 1 line of chemotherapy).
    4.Recent prior therapy, defined as:
    · Any investigational or approved non-biologic anti-cancer drug within 14 days prior to the first dose of GSK525762 and fulvestrant.
    · Any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK525762 and fulvestrant
    · Any anti-cancer biologic agents within 28 days prior to the first dose of GSK525762 and fulvestrant
    · Any radiotherapy within 30 days prior to the first dose of GSK525762 and fulvestrant. If the subject received radiotherapy <90 days prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response.
    · Any major surgery within 28 days prior to the first dose of GSK525762 and fulvestrant
    5.Concomitant active malignancy other than ER+BC
    6.Therapeutic-dose anticoagulation must be discontinued and coagulation parameters must be normalized prior to the first dose of GSK525762 and fulvestrant. Prophylactic anticoagulation is permitted.
    7.Current use of a prohibited medication or planned use of any forbidden medications during treatment with GSK525762 and fulvestrant.
    8.Evidence of severe or uncontrolled systemic diseases. Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator.
    9.Subjects with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term including subjects with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% of liver involvement in metastases.
    10.Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
    11. Cardiac abnormalities as evidenced by any of the following:
    ·Baseline QTcF interval ≥450 msec
    ·Clinically significant conduction abnormalities or arrhythmias
    ·Presence of cardiac pacemaker
    ·History or evidence of current ≥Class II congestive heart failure as defined by New York Heart Association (NYHA).
    ·History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months. Subjects with a history of stent placement requiring ongoing antithrombotic therapy (e.g., clopidogrel, prasugrel) will not be permitted to enroll.
    ·Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy
    12.Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator assessment).
    13.Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening.
    14.History of known HIV infection.
    15.Any serious known immediate or delayed hypersensitivity reaction(s) to GSK525762 or fulvestrant, or idiosyncrasy to drugs chemically related to the investigational drugs.
    16.Hemoptysis >1 teaspoon in 24 hours within the last 28 days.
    17.History of major gastrointestinal bleeding within the last 6 months.
    18. Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption.
    1. Tratamiento anterior con más de una línea de quimioterapia citotóxica tras el diagnóstico de estado avanzado/metastásico.
    2. La enfermedad ha avanzado a pesar del tratamiento previo con fulvestrant.
    3. ≥3 líneas de tratamiento contra el cáncer sistemático (incluida 1 línea de quimioterapia).
    4. Tratamiento previo reciente, definido como:
    - Cualquier fármaco en investigación o aprobado contra el cáncer no biológico en un plazo de 14 días antes de a primera dosis de GSK525762 y fulvestrant.
    - Cualquier nitrosourea o mitomicina C en un plazo de 42 días antes de la primera dosis de GSK525762 y fulvestrant.
    - Cualquier fármaco biológico contra el cáncer en un plazo de 28 días antes de la primera dosis de GSK525762 y fulvestrant.
    - Cualquier radioterapia en un plazo de 30 días antes de la primera dosis de GSK525762 y fulvestrant. Si el paciente recibió radioterapia <90 días antes del tratamiento del estudio, la lesión irradiada no puede ser la única lesión utilizada para evaluar la respuesta.
    - Cualquier cirugía mayor en un plazo de 28 días antes de la primera dosis de GSK525762 y fulvestrant.
    5. Neoplasia maligna activa concomitante que no sea CM+RE.
    6. Se deben interrumpir las dosis terapéuticas de anticoagulantes y los parámetros de coagulación se deben normalizar antes de la primera dosis de GSK525762 y fulvestrant. Se permite la anticoagulación profiláctica.
    7. Uso actual de un medicamento prohibido o uso planificado de cualquier medicamento prohibido durante el tratamiento con GSK525762 y fulvestrant.
    8. Signos de enfermedades sistémicas no controladas o graves. Cualquier trastorno psiquiátrico o médico grave o inestable preexistente (aparte de la neoplasia maligna) o cualquier alteración que pueda interferir en la seguridad del paciente, obteniendo el consentimiento informado o conforme a los procedimientos del estudio en opinión del investigador.
    9. Los pacientes con propagación visceral, sintomática, avanzada/metastásica, que presenten riesgo de complicaciones potencialmente mortales a corto plazo incluidos los pacientes con derrames masivos no controlados (pleural, pericárdico, peritoneal), linfangitis pulmonar, y más del 50 % de afectación del hígado en metástasis.
    10. Compresión de la médula espinal o metástasis cerebral o leptomeníngea no tratada o sintomática.
    11. Alteraciones cardiacas demostradas por:
    - Intervalo QTcF basal ≥450 ms
    - Arritmias o trastornos en la conducción clínicamente significativos
    - Presencia de marcapasos cardiaco
    - Historial o signos de insuficiencia cardiaca congestiva actual de ≥Clase II tal y como define la Asociación de Cardiología de Nueva York (NYHA).
    - Historial de síndromes coronarios agudos (incluidas anginas inestables e infarto de miocardio), angioplastia coronaria o colocación de endoprótesis en los últimos 3 meses. No se permitirá participar a pacientes a los que se les haya colocado una endoprótesis y que precisen de tratamiento antitrombótico continuo (p. ej., clopidogrel, prasugrel)
    - Enfermedad vascular clínicamente significativa, cardiomegalia, hipertrofia ventricular o cardiomiopatía
    12. Enfermedad hepática o biliar activa en la actualidad (con excepción del síndrome de Gilbert o cálculos biliares asintomáticos, metástasis en hígado u otra enfermedad hepática crónica, según la valoración del investigador).
    13. Presencia de antígenos de superficie de la hepatitis B (HBsAg) o resultado positivo de la prueba de anticuerpos de la hepatitis C en la selección.
    14. Historial de infección por VIH conocida.
    15. Cualquier reacción de hipersensibilidad tardía o inmediata conocida grave a GSK525762 o fulvestrant o idiosincrasia a fármacos químicamente relacionados con los fármacos en investigación.
    16. Hemoptisis >1 cucharilla en 24 horas en los últimos 28 días.
    17. Historial de sangrado gastrointestinal mayor en los últimos 6 meses.
    18. Cualquier alteración gastrointestinal (GI) clínicamente significativa que pueda alterar la absorción.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I
    - Safety profile (e.g. adverse events [AEs], serious adverse events [SAEs], dose-limiting toxicities (DLTs], dose reductions or delays), Overall Response Rate [ORR], defined as complete response [CR] rate plus partial response [PR] rate, pharmacokinetic [PK] data.
    Phase II
    - Progression free survival [PFS], defined as the median time from the first dose of study treatment until objective tumor progression or death from any cause, whichever comes first.
    Fase I:
    Perfil de seguridad (por ejemplo, acontecimientos adversos [AA], acontecimientos adversos graves [AAG], toxicidades limitantes de dosis [TLD], reducciones o retrasos de dosis), tasa general de respuesta (TGR), que se define como la tasa de respuesta completa [RC] más la tasa de respuesta parcial [RP], datos farmacocinéticos [FC].
    Fase II
    Supervivencia libre de progresión (SLP), definida como el tiempo medio transcurrido desde la administración de la primera dosis del tratamiento del estudio hasta la progresión objetivo del tumor o fallecimiento por cualquier motivo, lo que ocurra primero.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PHASE I
    -Safety profile: AE/SAE review continuous from signing informed consent; ECG (screening, week 1 days 1 and 4, weeks 2-5 day 1, every 4 weeks after week 9 until week 52 and at final study visit), ECHO/MUGA (screening, week 5 day 1, week 9 day 1, every 8 weeks from week 9-52 and final study visit), liver chemistry (screening, days 1 and 4 of weeks 1-5, every 4 weeks from week 9-52 and final study visit)
    -ORR: screening + every 8 weeks after week 9 and at the final study visit

    PHASE II
    -PFS: screening + every 8 weeks after week 9 and at the final study visit
    Fase I:
    - Perfil de seguridad: AA, AAG revisados desde la firma del consentimiento informado, ECG (screening, semana 1 días 1 y 4, semana de la 2 a la 5 día 1, y cada 4 semanas después de la semana 9 hasta la semana 52 y en la visita de fin de estudio; ECHO /MUGA (screening, semana 5 día 1 , semana 9 día 1, y cada 8 semanas después de la semana 9 hasta la semana 52 y en la visita de fin de estudio; bioquímica (screening, días 1 y 4 de las semanas 1 a la 5; y cada 4 semanas después de la semana 9 hasta la semana 52 y en la visita de fin de estudio).
    - TGR: Screening + cada 8 semanas después de la semana 9 y en la visita de fin de estudio
    Fase II:
    - SLP: screening y cada 8 semanas después de la semana 9 y en la visita de fin de estudio.
    E.5.2Secondary end point(s)
    Phase I
    - AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, electrocardiogram (ECG), cardiotoxicity, gastrointestinal, etc.)
    - Disease control rate ([DCR], defined as CR plus PR plus stable disease [SD] rate), duration of response, and progression-free survival [PFS], Time to progression [TTP].
    - Concentrations of GSK525762, GSK525762 relevant metabolites and fulvestrant following administration in combination
    - Targeted sequencing of tumor tissue to determine correlation between ESR1 mutations and clinical response
    Phase II
    - Overall survival [OS], time to progression [TTP]
    - ORR, DCR
    - GSK525762 and metabolites concentration following administration in
    combination with fulvestrant
    - Fulvestrant concentrations following administration alone or in
    combination with GSK525762
    - Targeted sequencing of tumor tissue to determine correlation between
    ESR1 mutations and clinical response
    Fase I
    - AA, AAG, reducciones o retrasos de dosis, retiradas por toxicidad y cambios en las evaluaciones de seguridad (por ejemplo, parámetros de laboratorio, constantes vitales, electrocardiograma (ECG), cardiotoxicidad, gastrointestinal, etc.)
    - Tasa de control de la enfermedad (TCE, definida como RC más RP más la tasa de estabilización de la enfermedad [EE]), duración de la respuesta, y supervivencia libre de progresión (SLP), tiempo de progresión (TDP)
    - Concentraciones de GSK525762, metabolitos relevantes de GSK525762 y fulvestrant tras la administración combinada
    - Secuenciación dirigida de tejido tumoral para determinar la correlación entre las mutaciones de VSE1 y la respuesta clínica
    Fase II:
    - Supervivencia general (SG)
    - TGR, TCE
    - Concentración de metabolitos de GSK525761 seguido de administración en combinación con fulvestrant
    - Concentración de fulvestrant seguido de administración sola o en combinación con GSK525762
    Secuenciación dirigida de tejido tumoral para determinar la correlación entre las mutaciones de VSE1 y la respuesta clínica
    E.5.2.1Timepoint(s) of evaluation of this end point
    PHASE I
    - AE/SAE review continuous from signing ICF; ECG, ECHO/MUGA and liver chemistry - according to protocol
    -DCR, PSF, TTP: screening + every 8 weeks after week 9 and at the final study visit
    -PK: week 1 day 1, week 3 day 1, week 5 day 1, every 8 weeks after week 9 (till week 26th)
    -ESR1: baseline after randomization

    PHASE II
    -Tumor assessment: screening + every 8 weeks after week 9 and at the final study visit
    -PK: weeks 1 and 5 day 1, every 8 weeks after week 9 (till week 26th)
    -ESR1: baseline after randomization
    Fase I.
    - Revision de AA, AAG desde la firma del CI; ECG; ECHO/MUGA y bioquímica de acuerdo al protocolo.
    - TCE, SLP, TDP: screening, + cada 8 semanas desde la semana 9 y en la visita fin de estudio
    - PK: semana 1 día 1, semana 3 día 1, semana 5 día 1 cada 8 semanas después de la semana 9 (hasta la semana 26)
    - VSE1: basal después de la randomizacion
    Fase II:
    - Evaluación del tumor: screening, + cada 8 semanas después de la semana 9 y en la visita de fin de estudio.
    - PK: semana 1 y 5 día 1, cada 9 semanas después de la semana 9 (hasta la semana 26)
    - VSE1: basal después de la randomizacion
    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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation and expansion study
    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 Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Phase I - dose escalation, expansion; Phase II - randomized, double-blind, placebo-controlled cohort
    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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Australia
    Canada
    France
    Korea, Republic of
    Spain
    United Kingdom
    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 study will be considered completed for purposes of a final analysis when approximately 70% of subjects enrolled in Phase II have progressed or died.
    El estudio se considerará completo para própositos de análisis final cuando el 70% de los sujetos incluídos en la Fase II progresen o mueran.
    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 months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    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: 195
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 105
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 105
    F.4.2.2In the whole clinical trial 300
    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)
    At the time of study completion, subjects with radiologically confirmed lack of disease progression (from Phase I and Phase II) who are still receiving GSK525762 and/or fulvestrant may continue treatment through a separate mechanism (e.g., roll-over protocol) to be determined at that time.
    En el momento del final del estudio, los sujetos que tengan radiológicamente confirmada falta de progresión (de la fase I y de la Fase II) que estén aun recibiendo GSK525762 y/o fulvestrant deberán continuar tratamiento mediante un mecanismo separado (ex; protocolo de extensión) que se determinará en ese momento.
    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 Decision2017-03-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-20
    P. End of Trial
    P.End of Trial StatusOngoing
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