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    Summary
    EudraCT Number:2016-003074-40
    Sponsor's Protocol Code Number:201973
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-08-10
    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 ConcernedFrance - ANSM
    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.
    Étude à doses croissantes et d'expansion de phase I/II, ayant pour but d'évaluer la tolérance, la pharmacocinétique, la pharmacodynamique et l'activité clinique du GSK525762 associé au fulvestrant chez des patientes atteintes de cancer du sein ER+.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial using GSK525762 in combination with fulvestrant in subjects with breast cancer.
    Étude de recherche du GSK525762 associé au fulvestrant chez des patientes atteintes de cancer du sein.
    A.4.1Sponsor's protocol code number201973
    A.5.4Other Identifiers
    Name:INDNumber:131933
    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
    Cancer du sein ER-positif
    E.1.1.1Medical condition in easily understood language
    Breast Cancer with growth promoted by estrogen - female hormone.
    Cancer du sein avec croissance favorisée par l'oestrogène - hormone féminine
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10070575
    E.1.2Term Estrogen receptor positive breast cancer
    E.1.2System Organ Class 100000115074
    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.
    Phase I
    Déterminer une dose recommandée de GSK525762 pour la phase 2, en association avec le fulvestrant, chez les femmes atteintes de cancer du sein à récepteurs aux oestrogènes positifs (ER+BC) avancé ou métastatique.

    Phase II
    Évaluer l'effet du traitement par GSK525762 et fulvestrant, administrés de manière concomitante, sur la survie sans progression chez les femmes atteintes d'un ER+BC avancé ou métastatique.
    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.
    -Déterminer la sécurité, la tolérance et la dose maximum tolérée (DMT) de GSK525762, administré en association avec le fulvestrant
    -Évaluer l'activité clinique de GSK525762 et du fulvestrant, administrés en concomitance
    -Évaluer l'effet du traitement par GSK525762 et fulvestrant, administrés de manière concomitante, sur d'autres indicateurs de la survie du sujet
    -Caractériser l'exposition à GSK525762, administré de manière concomitante avec le fulvestrant
    -Caractériser l'exposition au fulvestrant en monothérapie ou en concomitance avec GSK525762
    -Évaluer la présence d'une mutation du gène ESR1 comme indicateur potentiel de sensibilité et/ou de réponse à GSK525762 et au fulvestrant, en administration concomitante.
    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 relapsed during treatment or within 12 months of completion of adjuvant therapy with an AI, OR disease that progressed during treatment with an AI for advanced/metastatic disease. Prior ovarian suppression and/or tamoxifen are allowed as long as other criteria are met.
    b.CDK 4/6 inhibitor plus letrozole failures: disease that progressed during treatment with the combination of a CDK4/6 inhibitor plus letrozole, for advanced/metastatic disease. Prior ovarian suppression and/or tamoxifen are allowed as long as other criteria are met.
    7. Documented progression on last line of systemic anti-cancer therapy is required.
    8. Any menopausal status
    9. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
    10. 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
    11. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1
    12. Adequate organ function
    13. Able to swallow and retain orally administered medication
    14. 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 from the time of the screening pregnancy test until 7 months after the last dose of study medication
    - 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. Fourniture d'un consentement éclairé écrit
    2. Femmes âgées de 18 ans ou plus (au moment du consentement écrit)
    3. Diagnostic d'adénocarcinome du sein avancé ou métastatique, avec confirmation histologique ou cytologique.
    4. Documentation d'une tumeur ER-positive et/ou PR-positive sur la base d'une analyse locale de la biopsie tumorale la plus récente
    5. Documentation d'une tumeur HER2-négative sur la base d'une analyse locale de la biopsie tumorale la plus récente
    6. Traitement antérieur satisfaisant l'un des critères suivants :
    a. Échecs d'AI : récidive de la maladie pendant le traitement ou dans les 12 mois suivant l'achèvement d'un traitement adjuvant par AI, OU progression de la maladie pendant le traitement par AI pour un cancer avancé/métastatique. Une inhibition antérieure de l'activité ovarienne et/ou un traitement antérieur par tamoxifène sont autorisés à condition que les autres critères soient remplis.
    b. Échecs d'un inhibiteur de CDK 4/6 plus létrozole : progression de la maladie pendant le traitement avec une association d'inhibiteur de CDK4/6 plus létrozole pour un cancer avancé/métastatique. Une inhibition antérieure de l'activité ovarienne et/ou un traitement antérieur par tamoxifène sont autorisés à condition que les autres critères soient remplis.
    7. Une progression documentée lors de la dernière ligne de traitement anti-cancéreux systémique est obligatoire.
    8. Statut ménopausique
    9. Maladie mesurable à l'aide des critères RECIST (Response Evaluation Criteria in Solid Tumors) 1.1
    10. Toutes les toxicités liées au traitement antérieures doivent présenter un grade < 1 selon la classification NCI-CTCAE v4 (sauf pour l'alopécie [autorisée à tous les grades] et la neuropathie périphérique [autorisée jusqu'à un grade < 2]) au moment de l'attribution du traitement
    11. Score de 0 à 1 sur l'échelle de performances de l'ECOG (Eastern Cooperative Oncology Group)
    12. Fonction organique adéquate
    13. Capacité d'avaler et de garder des médicaments administrés par voie orale
    14. Une femme est admissible si :
    - elle n'est pas en âge de procréer
    - elle est en âge de procréer et accepte d'utiliser l'une des méthodes contraceptives, à partir du test de grossesse réalisé à la sélection jusqu'à 7 mois après la dernière dose du médicament de l'étude
    - elle possède un test de grossesse sérique négatif <7 jours avant la première dose du médicament de l'étude
    Les sujets de sexe féminin qui allaitent doivent arrêter l'allaitement avant la première dose du traitement de l'étude et ne peuvent pas allaiter pendant toute la période de traitement, et jusqu'à 28 jours au moins après la dernière dose du traitement de l'étude.
    E.4Principal exclusion criteria
    1. Prior therapy with any BET inhibitor, any selective estrogen receptor degrader (SERD) including fulvestrant, or inhibitors of the PI3K/AKT/mTOR pathway.
    2.Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of advanced/metastatic disease.
    3. ≥3 lines of systemic anti-cancer therapy in the advanced or metastatic setting
    4.Recent prior therapy, defined as:
    · Any investigational or approved non-biologic anti-cancer drug within 14 days or five half-life (whichever is greater) 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 42 days prior to the first dose of GSK525762 and fulvestrant
    · Any radiotherapy within 14 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 or defibrillator with a paced ventricular rhythm limiting ECG analysis
    ·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 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.Concurrent use if NSAIDs and high dose aspirin (except for cases where NSAIDs provide benefit over other analgesics and in these cases, consideration should be given to the prophylactic administration of a proton pump inhibitor) and high dose aspirin (allowed up to ≤100 mg PO daily).
    18. Subjects with history of known bleeding disorder(s) including clinically significant hemorrhage with the past 6 months.
    19. Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption.
    1. Traitement antérieur avec tout inhibiteur des BET, tout antagoniste sélectif des récepteurs des ┼ôstrogènes (selective estrogen receptor degrader: SERD), y compris le fulvestrant, ou des inhibiteurs de la voie PI3K/AKT/mTOR
    2. Traitement antérieur avec plus d'une ligne de chimiothérapie cytotoxique après un diagnostic de cancer avancé/métastatique
    3. ≥ 3 lignes de traitement anti-cancéreux systémique en cas de cancer avancé ou métastatique.
    4. Traitement antérieur récent, définit comme :
    • Tout anti-cancéreux non biologique expérimental ou approuvé dans les 14 jours ou cinq demi-vies (la durée la plus longue étant considérée) précédant la première dose de GSK525762 et de fulvestrant
    • Toute nitrosourée ou mitomycine C dans les 42 jours précédant la première dose de GSK525762 et de fulvestrant
    • Tout anti-cancéreux biologique dans les 42 jours précédant la première dose de GSK525762 et de fulvestrant
    • Toute radiothérapie dans les 14 jours précédant la première dose de GSK525762 et de fulvestrant. Si le sujet a reçu une radiothérapie < 90 jours avant le traitement de l'étude, la lésion irradiée ne peut pas être la seule lésion utilisée pour l'évaluation de la réponse.
    • Toute intervention chirurgicale majeure dans les 28 jours précédant la première dose de GSK525762 et de fulvestrant
    5. Maladie maligne active concomitante autre qu'un ER+BC
    6. L'anticoagulation à doses thérapeutiques doit être interrompue et les paramètres de coagulation doivent être normalisés avant la première dose de GSK525762 et de fulvestrant. Une anticoagulation prophylactique est autorisée
    7. Utilisation en cours ou prévue d'un médicament interdit pendant le traitement par GSK525762 et fulvestrant
    8. Preuve de maladie systémique sévère ou incontrôlée. Tout trouble médical (autre que le cancer), psychiatrique ou autre, pré-existant, grave et/ou instable susceptible d'interférer avec la sécurité du sujet, l'obtention du consentement éclairé ou le respect des procédures de l'étude, à la discrétion de l'investigateur
    9. Sujets présentant une dissémination viscérale, symptomatique, avancée/métastatique, à risque de complications mettant en jeu le pronostic vital à court terme, notamment sujets atteints d'épanchements massifs incontrôlés (pleuraux, péricardiques, péritonéaux), de lymphangite pulmonaire et d'un envahissement de plus de 50 % du foie par les métastases
    10. Métastases leptoméningées ou cérébrales symptomatiques ou non traitées ou compression de la moelle épinière
    11. Anomalies cardiaques démontrées par l'un des éléments suivants :
    • Intervalle QTcF à l'inclusion ≥ 450 ms
    • Anomalies de la conduction ou arythmies cliniquement significatives
    • Présence d'un stimulateur cardiaque ou d'un défibrillateur présentant un rythme ventriculaire stimulé limitant l'analyse ECG
    • Antécédents ou preuves d'insuffisance cardiaque congestive en cours de ≥ classe II telle que définie par la New York Heart Association (NYHA).
    • Antécédents de syndrome coronaire aigu (y compris angor instable et infarctus du myocarde), d'angioplastie coronaire, ou pose d'une endoprothèse dans les 3 mois précédents. Les sujets porteurs d'une endoprothèse nécessitant un traitement antithrombotique continu (p. ex., clopidogrel, prasugrel) seront exclus de l'étude
    • Cardiomégalie, hypertrophie ventriculaire ou cardiomyopathie cliniquement significative
    12. Pathologie hépatique ou biliaire active (à l'exception du syndrome de Gilbert ou de calculs biliaires asymptomatiques, de métastases hépatiques ou d'une maladie hépatique chronique stable, tel que statué par l'investigateur)
    13. Présence d'antigène de surface de l'hépatite B (HBsAg) ou d'un résultat positif au test de détection des anticorps de l'hépatite C lors de la sélection
    14. Antécédents d'infection à VIH connue
    15. Toute réaction d'hypersensibilité immédiate ou retardée grave connue au GSK525762 ou au fulvestrant ou idiosyncrasie à des médicaments chimiquement liés aux médicaments expérimentaux
    16. Hémoptysie > 1 cuillère à café en 24 heures au cours des 28 derniers jours
    17. Utilisation concomitante d'AINS (sauf lorsque les AINS présentent des avantages par rapport à d'autres analgésiques ; le cas échéant, il convient d'envisager l'administration prophylactique d'un inhibiteur de la pompe à protons) et d'une forte dose d'aspirine (autorisée jusqu'à ≤ 100 mg par jour par voie orale)
    18. Antécédents de troubles hémorragiques connus, y compris hémorragie cliniquement significative (p. ex., GI, neurologique) au cours des 6 derniers mois
    19. Toute anomalie gastrointestinale (GI) cliniquement significative susceptible d'altérer l'absorption du médicament de l'étude
    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.
    Phase I
    - Profil de sécurité (p. ex., effets indésirables [EI], effets indésirables graves [EIG], toxicités limitant la dose [TLD], réductions ou retards de dose), taux de réponse globale (TRG), défini par le taux de réponse complète [RC] additionné au taux de réponse partielle [RP], données pharmacocinétiques [PC].
    Phase II
    -Survie sans progression (SSP), définie par le délai médian entre la première dose du traitement de l'étude et la progression tumorale objective ou le décès toutes causes confondues, selon l'événement qui survient en premier.
    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
    PHASE I
    -Profils de sécurité: EI/EIG surveillance continue depuis la signature du consentement éclairé ; ECG (sélection, semaine 1 jours 1 et 4, semaines 2-5 jour 1, toutes les 4 semaines après la semaine 9 jusqu'à la semaine 52 et à la visite finale de l'étude), ECHO/MUGA (sélection, semaine 5 jour 1, semaine 9 jour 1, toutes les 8 semaines depuis la semaine 9-52 et
    visite finale de l'étude), biochimique du foie (sélection, jours 1 et 4 des semaines 1-5, toutes les 4 semaines depuis la semaine 9-52 et visite finale de l'étude)
    -ORR : sélection+ toutes les 8 semaines après la semaine 9 et la visite finale de l'étude

    PHASE II
    -PFS: selection + toutes les 8 semaines après la semaine 9 et à la visite finale de l'étude
    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
    Phase I
    - EI, EIG, réductions ou retards de dose, retraits dus à des toxicités et modifications de l'évaluation de la sécurité (p. ex., paramètres de laboratoire, signes vitaux, électrocardiogramme (ECG), cardiotoxicité, effets gastrointestinaux, etc.)
    - Taux de contrôle de la maladie (TCM ; défini par la RC, plus la RP, plus le taux de maladie stable [MS]), durée de la réponse et survie sans progression (SSP), délai de progression (DP).
    - Concentrations de GSK525762, des métabolites pertinents de GSK525762 et de fulvestrant après une administration concomitante
    - Séquençage ciblé de tissu tumoral pour déterminer la corrélation entre les mutations du gène ESR1 et la réponse Clinique

    Phase II
    - Survie globale (SG), délai de progression (DP)
    - TRG, TCM
    - Concentrations de GSK525762 et des métabolites après une administration concomitante avec du fulvestrant
    - Concentrations de fulvestrant après une administration en monothérapie ou en concomitance avec GSK525762
    - Séquençage ciblé de tissu tumoral pour déterminer la corrélation entre les mutations du gène ESR1 et la réponse clinique
    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
    PHASE I
    -EI/EIG surveillance continue depuis la signature du consentement éclairé ; ECG, ECHO/MUGA et biochimique du foie conformément au protocole.
    -DCR, PSF, TTP : sélection + toutes les 8 semaines après la semaine 9 et à la visite finale de l'étude
    -PK : semaine 1 jour 1, semaine 3 jour 1, semaine 5 jour 1, toutes les 8 semaines après la semaine 9 (jusqu'à la semaine 26)
    -ESR1 : base après randomisation

    PHASE II
    -Évaluation des tumeurs: sélection + toutes les 8 semaines après la semaine 9 et à la visite finale de l'étude
    -PK : semaines 1 et 5 jour 1, toutes les 8 semaines après la semaine 9 (jusqu'à la semaine 26)
    -ESR1 : base après randomisation
    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
    Étude d'augmentation posologique et d'expansion
    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 - augmentation posologique et d'expansion ; Plase II - cohorte randomisée, en double aveugle
    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 concerned3
    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 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 study will be considered completed for purposes of a final analysis when approximately 70% of subjects enrolled in Phase II have progressed or died.
    L'étude sera considérée achevée aux fins d'une analyse finale lorsque environ 70% des sujets inscrits à la phase II auront progressé ou décédé.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months11
    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 state20
    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.
    Une fois l'essai complété, les sujets ayant confirmé radiologiquement sans progression de la maladie (de la phase I et de la phase II) recevant encore le GSK525762 et/ou le fulvestrant pourraient continuer le traitement par un mécanisme distinct (par exemple, protocole roll-over) à déterminer à ce moment-là.
    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 Decision2017-08-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-05
    P. End of Trial
    P.End of Trial StatusOngoing
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