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    Summary
    EudraCT Number:2022-000199-20
    Sponsor's Protocol Code Number:ML43171
    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:2022-06-09
    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 number2022-000199-20
    A.3Full title of the trial
    A PHASE III RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF GIREDESTRANT PLUS EVEROLIMUS COMPARED WITH EXEMESTANE PLUS EVEROLIMUS IN PATIENTS WITH ESTROGEN RECEPTOR-POSITIVE, HER2- NEGATIVE, LOCALLY ADVANCED OR METASTATIC BREAST CANCER
    ESTUDIO MULTICÉNTRICO EN FASE III, ALEATORIZADO Y SIN ENMASCARAMIENTO PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DE LA COMBINACIÓN GIREDESTRANT MÁS EVERÓLIMUS, Y COMPARARLAS CON LAS DE LA COMBINACIÓN EXEMESTANO MÁS EVERÓLIMUS, EN PACIENTES CON CÁNCER DE MAMA CON RECEPTORES ESTROGÉNICOS, SIN MUTACIÓN DEL GEN HER2, LOCALMENTE AVANZADO O METASTÁSICO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Efficacy and Safety of Giredestrant Plus Everolimus Compared with Exemestane Plus Everolimus in Patients with Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer
    Estudio para Evaluar la Eficacia y la Seguridad de la Combinación Giredestrant Más Everólimus, Y Compararlas con las de la Combinación Exemestano Más Everólimus, en Pacientes con Cáncer de Mama con Receptores Estrogénicos, sin Mutación Del Gen Her2, Localmente Avanzado o Metastásico
    A.4.1Sponsor's protocol code numberML43171
    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 SponsorGenentech, Inc.
    B.1.3.4CountryUnited States
    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 supportGenentech, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffman-La Roche Ltd/Genentech
    B.5.2Functional name of contact pointTrial Information Support Line TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post codeCH-4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+34913257300
    B.5.5Fax number+34913248196
    B.5.6E-mailspain.start_up_unit@roche.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namegiredestrant
    D.3.2Product code RO7197597
    D.3.4Pharmaceutical form Capsule, hard
    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 INNGiredestrant
    D.3.9.2Current sponsor codeRO7197597
    D.3.9.3Other descriptive nameGDC-9545
    D.3.9.4EV Substance CodeSUB216524
    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: 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 Yes
    D.2.1.1.1Trade name Everolimus Zentiva
    D.2.1.1.2Name of the Marketing Authorisation holderZentiva Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 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 INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Exemestane Accord France
    D.2.1.1.2Name of the Marketing Authorisation holderAccord France
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEXEMESTANE
    D.3.9.2Current sponsor codeRo 532-4663
    D.3.9.4EV Substance CodeSUB07492MIG
    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: 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 Everolimus Zentiva
    D.2.1.1.2Name of the Marketing Authorisation holderZentiva Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 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 INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP 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 Everolimus Zentiva
    D.2.1.1.2Name of the Marketing Authorisation holderZentiva Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 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 INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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
    Estrogen Receptor (ER)-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer previously treated with a CDK4/6 inhibitor and endocrine therapy
    Cáncer de Mama Receptor de estrógeno (RE)-Positivo, HER2-Negativo, Localmente Avanzado o Metastásico previamente tratados con inhibidor CDK4/6 y terapia endocrina
    E.1.1.1Medical condition in easily understood language
    Breast cancer is a cancer that develops in the tissues of the breast. ER-positive, HER2-negative breast cancer is breast cancer which tests positive for ER and negative for HER2.
    El cancer de mama es un cancer que se desarrolla en los tejidos de la mama. El cancer de mama RE positivo, HER2-negativo es el cancer de mama que da positivo para RE y negativo para HER2
    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 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10070575
    E.1.2Term Estrogen receptor positive breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10072740
    E.1.2Term Locally advanced breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10083232
    E.1.2Term HER2 negative breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 efficacy of giredestrant plus everolimus compared with exemestane plus everolimus on the basis of investigator-assessed progression-free survival (PFS)
    Evaluar la eficacia de la combinación giredestrant más everólimus y compararla con la de la combinación exemestano más everólimus en base a la Supervivencia sin progresión (SSP) determinado por el investigador
    E.2.2Secondary objectives of the trial
    ● To evaluate the efficacy of giredestrant plus everolimus compared with exemestane plus everolimus on the basis of investigator-assessed progression-free survival (PFS) in subgroups based on Estrogen Receptor 1 (ESR1)-mutation status, overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), time to confirmed deterioration (TTCD) in pain presence and interference, TTCD in Physical Functioning (PF), TTCD in Role Functioning (RF) and TTCD in health-related quality of life (HRQoL)
    ● To evaluate the safety of giredestrant plus everolimus compared with exemestane plus everolimus
    ● To characterize the giredestrant pharmacokinetic (PK) profile when given in combination with everolimus
    -Evaluar la eficacia de la combinación giredestrant más everólimus y compararla con la de la combinación exemestano más everólimus en base a la SSP evaluada por el investigador, en subgrupos categorizados de forma prospectiva en función del estado inicial de mutación del receptor de estrógeno 1 (ESR1), Supervivencia general (SG), Tasa de respuesta objetiva (TRO), Duración de la respuesta (DdR), Tasa de beneficio clínico (TBC), Tiempo hasta el deterioro confirmado (TTCD), TTCD en el funcionamiento físico (FF), TTCD en la capacidad funcional (CF) y TTCD en la calidad de vida relacionada con la salud (CVRS)
    - Evaluar la seguridad de la combinación giredestrant más everólimus y compararla con la de la combinación exemestano más everólimus
    - Caracterizar el perfil FC del giredestrant cuando se administra en combinación con everólimus
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ● Age >= 18 years
    ● Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
    ● Documented estrogen receptor-positive (ER+) tumor according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society for Medical Oncology (ESMO) guidelines, assessed locally and defined as >= 1% of tumor cells stained positive based on the most recent tumor biopsy (or archived tumor sample)
    ● Documented human epidermal growth factor receptor 2 (HER2)-negative tumor assessed locally
    ● Availability of blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) ESR1 mutation status determination by central testing prior to study treatment randomization
    ● Patients who have bilateral breast cancers that are both ER+ and HER2-negative are eligible. If patients have bilateral tumors that are of different biomarker status, then proof of the ER and HER2 status of the metastases is required for study entry
    ● Prior endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in either setting as follows:
    Metastatic Setting:
    o Disease progression >/=6 months after initiating ET plus CDK4/6 inhibitor in the locally advanced or metastatic setting. If ET plus CDK4/6 inhibitor is not the most recent therapy, then patient must also have had disease progression after >/=4 months on most recent ET
    Adjuvant Setting:
    o Relapse either while taking or within 12 months of exposure to combination adjuvant ET and CDK4/6 inhibitor. Patients must have taken at least 12 months of adjuvant ET, 6 months of which was in combination with a CDK4/6 inhibitor
    ● Measurable disease as defined per RECIST v.1.1 or evaluable bone metastases which must have at least one predominantly lytic bone lesion confirmed by CT or MRI which can be followed
    ● Eastern Cooperative Oncology Group Performance Status 0-1
    ● Life expectancy of >6 months
    ● Adequate organ function
    ● International normalized ratio (INR) [or prothrombin time (PT)] < 1.5 x upper limit of normal (ULN) and partial thromboplastin time (PTT) [or activated partial thromboplastin time (aPTT)] < 1.5 x ULN
    ● Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE v5.0 Grade <= 1
    ● For women: postmenopausal or premenopausal/perimenopausal status
    Postmenopausal, as defined by at least one of the following criteria:
    o >/=12 months of amenorrhea without an alternate medical cause plus follicle stimulating hormone (FSH) and plasma estradiol levels within postmenopausal range by local laboratory assessment, in the absence of oral contraceptive pills, hormone replacement therapy, or gonadotropin releasing hormone agonist or antagonist
    o Documented bilateral oophorectomy
    o Premenopausal/perimenopausal willing to undergo and maintain treatment with approved luteinizing hormone-releasing hormone (LHRH)-agonist therapy
    ● For men: willing to undergo and maintain treatment with approved LHRH agonist therapy for the duration of study treatment, or documented bilateral orchiectomy
    ● For women of childbearing potential: agreement to remain abstinent or use non-hormonal contraceptive methods with a failure rate of < 1% per year during the treatment period and for 9 days after the final dose of giredestrant, 8 weeks after the final dose of everolimus, and 1 month after the final dose of exemestane. Women must refrain from donating eggs during this same period
    ● For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 9 days after the final dose of giredestrant, 4 weeks after the final dose of everolimus, and 1 month after the final dose of exemestane. Men must refrain from donating sperm during this same period
    -Tener 18 años
    -Tener adenocarcinoma de mama localmente avanzado o metastásico, no tributario de tratamiento (tto) con intención curativa.
    -Tumor con receptores estrogénicos documentado de acuerdo con las pautas de la Sociedad Estadounidense de Oncología Clínica o el Colegio de Patólogos Estadounidenses (ASCO/CAP) o la ESMO (Sociedad Europea de Oncología Médica), evaluado localmente y definido como 1 % de células tumorales con tinción positiva en la biopsia tumoral más reciente (o muestra de tumor de archivo).
    -Tumor sin mutación del gen HER2 documentado evaluado localmente
    - Disponibilidad de muestras de sangre para la determinación del estado de mutación del gen ESR1 en el ADNtc mediante pruebas centrales antes de la aleatorización.

    -Los pacientes que tienen cáncer de mama bilateral con receptores estrogénicos y que no presentan mutaciones de HER2 son aptos para el estudio porque los ttos del estudio son adecuadamente selectivos para las metástasis. Si los pacientes presentan tumores bilaterales que tienen un estado de biomarcador diferente, se requerirán pruebas del estado de RE y HER2 de las metástasis para entrar en el estudio.
    -HT anterior en combinación con CDK4/6i, en cualquiera de las situaciones de la siguiente manera:
    Metástasis: Progresión de la enf 6 meses después de iniciar la HT más el CDK4/6i en caso de tumor localmente avanzado o metastásico. Si la HT más el CDK4/6i no es la terapia más reciente, el paciente deberá haber presentado también una progresión de la enfermedad después de 4 meses con la HT más reciente.
    Tto complementario: Recidiva ya sea durante la exposición a la combinación de HT complementaria y CDK4/6i o en los 12 meses posteriores. Los pacientes deben haber recibido al menos 12 meses de HT complementaria, 6 de los cuales en combinación con un CDK4/6i.
    -Enf mensurable según se define en la v.1.1 de los RECIST o metástasis óseas evaluables.
    Los pacientes que solo tengan enfermedad ósea deben tener al menos una lesión ósea predominantemente lítica confirmada por TC o RM.
    Las lesiones tumorales previamente irradiadas o sujetas a otra terapia locorregional se considerarán mensurables solo si la progresión de la enfermedad en el sitio tratado después de completar la terapia se ha documentado con claridad.
    -Estado funcional del Eastern Cooperative Oncology Group 0-1.
    -Esperanza de vida de 6 meses.
    -Actividad orgánica adecuada
    -Resolución de todos los efectos tóxicos agudos del tto antineoplásico o procedimiento quirúrgico anterior hasta un grado 1 de la v5.0 de los CTCAE del
    -Mujeres: estado posmenopáusico o premenopáusico/perimenopáusico, definido de la siguiente manera:Estado posmenopáusico, definido por al menos uno de los siguientes criterios:
    12 meses de amenorrea sin una causa médica alternativa más concentración de hormona foliculoestimulante (FSH) y concentraciones plasmáticas de estradiol dentro del intervalo posmenopáusico, según análisis del laboratorio local, en ausencia de píldoras anticonceptivas orales, hormonoterapia de reposición o agonistas o antagonistas de la hormona liberadora de gonadotropina. Ovariectomía bilateral documentada
    Estado premenopáusico o perimenopáusico (es decir, que no se cumplen los criterios del estado posmenopáusico): tto con un agonista de la LHRH aprobado durante todo el tto del estudio.
    -Varones: tto con agonista de la LHRH aprobado durante todo el tto del estudio u orquiectomía bilateral documentada
    El tto con agonistas de la LHRH puede iniciarse hasta 28 días antes del día 1 del ciclo 1 (o de acuerdo con la práctica clínica del fármaco seleccionado). Para minimizar la posibilidad de que la exposición al medicamento disminuya a concentraciones subterapéuticas hacia el final del ciclo de tto, se prefieren las inyecciones mensuales del agonista de la LHRH y se sincronizan con el día 1 de cada ciclo de 28 días.
    -Mujeres fértiles: deben acordar guardar abstinencia (abstenerse de tener relaciones heterosexuales) o usar métodos anticonceptivos como se define a continuación:
    Las mujeres deben abstenerse de mantener relaciones sexuales, o bien utilizar métodos anticonceptivos no hormonales con una tasa de fracaso <1 % anual durante el período de tto y durante los 9 días posteriores a la última dosis de giredestrant, las 8 semanas posteriores a la última dosis de everólimus y 1 mes después de la última dosis de exemestano. Las mujeres deben abstenerse de donar óvulos durante este mismo período.
    -Varones: deben aceptar guardar abstinencia (abstenerse de tener relaciones heterosexuales o bien utilizar un preservativo más otro método anticonceptivo cuyo uso conjunto tenga una tasa de fracaso <1 % anual durante el período de tto y durante los 9 días posteriores a la última dosis de giredestrant, las 4 semanas posteriores a la última dosis de everólimus y 1 mes después de la última dosis de exemestano. Los varones deben abstenerse de donar semen durante este mismo período.
    E.4Principal exclusion criteria
    ● Prior treatment with another oral selective estrogen receptor degrader (SERD) in any setting. Prior fulvestrant is allowed if treatment was terminated at least 28 days prior to randomization
    ● No more than 2 prior lines of systemic endocrine therapy in the locally advanced or metastatic breast cancer setting
    ● Prior chemotherapy for locally advanced or metastatic disease
    ● Treatment with the multidrug efflux pump P-glycoprotein (P-gp) and strong Cytochrome P450 3A4 (CYP3A4) inhibitors within 14 days or 5 drug elimination half-lives prior to randomization
    ● Treatment with any investigational therapy within 28 days prior to initiation of study treatment
    ● Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 28 days prior to randomization
    ● History of any other malignancy other than breast cancer within 5 years prior to screening except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, papillary thyroid cancer treated with surgery, or Stage I endometrial cancer
    ● Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
    ● Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
    ● Active cardiac disease or history of cardiac dysfunction
    ● Patients known to be positive for human immunodeficiency viruses (HIV) are excluded if they meet any of the following criteria:
    o CD4+ T-cell count of < 350 cells/µL
    o Detectable HIV viral load
    o History of an opportunistic infection within the past 12 months
    o On stable antiretroviral therapy for < 4 weeks
    ● Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis virus, current alcohol abuse, or cirrhosis
    ● Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection, potentially affecting enteral absorption, or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea
    ● Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy
    ● Serious infection requiring oral or intravenous (IV) antibiotics, or other clinically significant infection, within 14 days prior to randomization
    ● Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
    ● Known allergy or hypersensitivity to any of the study drugs or any of their excipients
    ● For premenopausal/perimenopausal or male patients known hypersensitivity to LHRH agonists
    ● Pregnant or breastfeeding, or intending to become pregnant during the study or within 9 days after the final dose of giredestrant, and 1 month after the final dose exemestane, and 8 weeks after the final dose of everolimus
    -Tratamiento previo con otro DSRE por vía oral en cualquier situación. Se permite el fulvestrant si el tratamiento finalizó al menos 28 días antes de la aleatorización.
    -No más de 2 líneas previas de hormonoterapia sistémica en caso de cáncer de mama metastásico o localmente avanzado.
    -Quimioterapia previa para metástasis o enfermedad localmente avanzada.
    -Tratamiento con la bomba de expulsión de diversos fármacos P-gp (glucoproteína P) e inhibidores potentes de CYP3A4 en los 14 días o 5 semividas de eliminación del fármaco antes de la aleatorización.
    -Tratamiento con cualquier terapia en investigación en los 28 días anteriores al inicio del tratamiento del estudio.
    -Intervención quirúrgica mayor, quimioterapia, radioterapia u otra terapia antineoplásica en los 28 días anteriores a la aleatorización.
    -Antecedentes de cualquier otra neoplasia maligna que no sea cáncer de mama en los 5 años anteriores a la selección, excepto el carcinoma in situ de cuello uterino tratado de forma adecuada, el cáncer de piel distinto del melanoma, el cáncer papilar de tiroides tratado con intervención quirúrgica o el cáncer de endometrio en estadio I.
    -Propagación visceral avanzada, sintomática, con riesgo de complicaciones potencialmente mortales a corto plazo
    -Metástasis activas no controladas o sintomáticas conocidas en el sistema nervioso central (SNC), meningitis carcinomatosa o carcinomatosis leptomeníngea.
    -Cardiopatía activa o antecedentes de disfunción cardíaca
    -Debe excluirse a los pacientes que se sabe que son positivos para el VIH si cumplen alguno de los criterios siguientes:
    Cifra de linfocitos T CD4+ 350 células/l
    Carga vírica del VIH detectable
    Antecedentes de infección oportunista en los últimos 12 meses
    En tratamiento antirretrovírico estable durante 4 semanas
    -Antecedentes clínicamente significativos conocidos de hepatopatía compatible con la clase B o C de Child-Pugh, incluidos la hepatitis vírica o de otro tipo el alcoholismo o la cirrosis
    -Enteropatía inflamatoria activa, diarrea crónica, síndrome de intestino corto o intervención quirúrgica mayor de la porción alta del tubo digestivo, incluida la resección gástrica, que podría afectar la absorción entérica, o una enfermedad crónica preexistente que produzca diarrea de grado 2 o superior en el momento basal.
    -Neumopatía intersticial o disnea grave en reposo o que requiera oxigenoterapia.
    -Infección grave que requiera antibióticos orales o intravenosos, u otra infección clínicamente significativa, en los 14 días anteriores a la aleatorización.
    -Cualquier enfermedad grave o anomalía en los análisis clínicos que, a juicio del investigador, impida la participación segura del paciente y la finalización del estudio.
    -Alergia o hipersensibilidad conocida a cualquiera de los fármacos del estudio o a alguno de sus excipientes.
    -En el caso de pacientes premenopáusicas/perimenopáusicas o varones: hipersensibilidad conocida a los agonistas de la LHRH.
    -Mujeres embarazadas o en período de lactancia, o con intención de quedarse embarazadas durante el estudio o durante los 9 días posteriores a la última dosis de giredestrant, las 8 semanas posteriores a la última dosis de everólimus y 1 mes después de la última dosis de exemestano.
    E.5 End points
    E.5.1Primary end point(s)
    1. PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)
    1. Supervivencia sin progresión (SSP), definida como el tiempo transcurrido entre la aleatorización y la primera progresión del tumor o la muerte por cualquier causa (lo que ocurra primero), según lo determine el investigador de acuerdo con la versión 1.1. de los criterios de evaluación de la respuesta en tumores sólidos (RECIST v1.1).
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 42 months
    1. Hasta aproximadamente 42 meses
    E.5.2Secondary end point(s)
    1. Investigator-assessed PFS, in subgroups categorized prospectively by baseline ESR1-mutation status, as measured by ctDNA
    2. OS after randomization, defined as the time from randomization to death from any cause
    3. ORR, defined as the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST v1.1
    4. DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
    5. CBR, defined as the proportion of patients with stable disease for >= 24 weeks or a CR or PR on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST v1.1
    6. TTCD in pain presence and interference after randomization, defined as the time from randomization to the first documentation of >= 10-point increase in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 Questionnaire (QLQ-C30) linearly transformed pain scale score held for two consecutive time points, or a >=10-point increase followed by death attributable to cancer progression with 28 days from the last assessment
    7. TTCD in PF after randomization, defined as the time from randomization to the first documentation of >= 10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed PF scale score held for two consecutive time points, or a >= 10-point decrease followed by death attributable to cancer progression with 28 days from the last assessment
    8. TTCD in RF after randomization, defined as the time from randomization to the first documentation of >= 10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed RF scale score held for two consecutive time points, or a >= 10-point decrease followed by death attributable to cancer progression with 28 days from the last assessment
    9. TTCD in HRQoL after randomization, defined as the time from randomization to the first documentation of >= 10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed GHS/QoL scale score held for two consecutive time points, or a >= 10-point decrease followed by death attributable to cancer progression with 28 days from the last assessment
    10. Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0
    11. Change from baseline in targeted vital signs
    12. Change from baseline in targeted clinical laboratory test results
    13. Plasma concentration of giredestrant at specified timepoints
    1. SSP evaluada por el investigador, en subgrupos categorizados de forma prospectiva en función del estado inicial de ESR1, según las mediciones del ADN tumoral circulante (ADNtc).
    2. SG después de la aleatorización, definida como el tiempo transcurrido desde la aleatorización hasta la muerte por cualquier causa.
    3. TRO, definida como la proporción de pacientes con respuesta completa (RC) o una respuesta parcial (RP) en dos ocasiones consecutivas con 4 semanas de diferencia, según lo determine el investigador de acuerdo con la versión 1.1. de los RECIST.
    4. DdR, definida como el tiempo transcurrido desde la primera aparición de una respuesta objetiva documentada hasta la progresión de la enfermedad o la muerte por cualquier causa (lo que ocurra primero), según lo determine el investigador de acuerdo con la versión 1.1. de los RECIST.
    5. TBC, definida como la proporción de pacientes con enfermedad estable durante 24 semanas, o RC o RP en dos ocasiones consecutivas con 4 semanas de diferencia, según lo determine el investigador de acuerdo con la versión 1.1. de los RECIST.
    6. TTCD en presencia de dolor e interferencia después de la aleatorización, definido como el tiempo transcurrido desde la aleatorización hasta la primera documentación de un aumento de 10 puntos en la puntuación transformada linealmente de la escala del dolor en el cuestionario básico de calidad de vida de 30 ítems (QLQ-C30) de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC) mantenido durante dos momentos consecutivos, o un aumento de 10 puntos seguido de muerte atribuible a la progresión del cáncer 28 días después de la última evaluación.
    7. TTCD en el FF después de la aleatorización, definido como el tiempo transcurrido desde la aleatorización hasta la primera documentación de una disminución de 10 puntos desde el momento basal en la puntuación transformada linealmente de la escala del FF en el QLQ-C30 de la EORTC mantenida durante dos momentos consecutivos, o una disminución de 10 puntos seguida de muerte atribuible a la progresión del cáncer 28 días después de la última evaluación.
    8. TTCD en CF después de la aleatorización, definido como el tiempo transcurrido desde la aleatorización hasta la primera documentación de una disminución de 10 puntos desde el momento basal en la puntuación transformada linealmente de la escala de la CF en el QLQ-C30 de la EORTC mantenida durante dos momentos consecutivos, o una disminución de 10 puntos seguida de muerte atribuible a la progresión del cáncer 28 días después de la última evaluación.
    9. TTCD en la CVRS después de la aleatorización, definido como el tiempo transcurrido desde la aleatorización hasta la primera documentación de una disminución de 10 puntos desde el momento basal en la puntuación transformada linealmente de la escala de la CVRS en el QLQ-C30 de la EORTC mantenida durante dos momentos consecutivos, o una disminución de 10 puntos seguida de muerte atribuible a la progresión del cáncer 28 días después de la última evaluación.
    10. Incidencia e intensidad de los acontecimientos adversos según las definiciones de intensidad de NCI CTCAE v5.0.
    11. Cambio desde el momento basal en ciertas constantes vitales específicas.
    12. Cambio desde el momento basal en ciertos resultados analíticos específicos.
    13. Concentración plasmática de giredestrant en momentos especificados
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-10. Up to approximately 42 months
    11-12. Baseline up to 42 months
    13. Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and 3
    1-10. Hasta aproximadamente 42 meses
    11-12. Momento basal hasta los 12 meses
    13. Día 1 y Día 15 de Ciclo 1, Día 1 de Ciclo 2 y 3.
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned12
    E.8.5The trial involves multiple Member States No
    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
    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
    LVLS
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months42
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months42
    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: 112
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 112
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2022-06-09. Yes
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 224
    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)
    Currently, the Sponsor does not have any plans to provide Genentech IMP (giredestrant) or any other study treatments to patients who have completed the study. The Sponsor may evaluate whether to continue providing giredestrant in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, available at the following website:http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    Actualmente, el promotor no tiene planes para proporcionar el IMP de Genentech (giredestrant) ni ningún otro tratamiento del estudios a los pacientes que hayan completado el estudio. El promotor puede evaluar si continua proporcionando giredestrant de acuerdo a la Política Global de Roche sobre el acceso continuo al medicamento en investigación, disponible en el siguiente enlace
    website:http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    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 Decision2022-07-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-20
    P. End of Trial
    P.End of Trial StatusOngoing
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