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    Summary
    EudraCT Number:2019-002123-15
    Sponsor's Protocol Code Number:GEICAM/2019-01
    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:2020-05-28
    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 number2019-002123-15
    A.3Full title of the trial
    Phase II, randomized, open-label, international, multicenter study to compare efficacy of standard chemotherapy vs. letrozole plus abemaciclib as neoadjuvant therapy in HR-positive/HER2-negative high/intermediate risk breast cancer patients. “CARABELA Study”
    Estudio de fase II, aleatorizado, abierto, internacional y multicéntrico, para comparar la eficacia de la quimioterapia estándar frente a letrozol más abemaciclib como terapia neoadyuvante en pacientes con cáncer de mama con RH-positivo/HER2-negativo de riesgo alto/intermedio. “Estudio CARABELA”
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial to compare efficacy and safety of standard chemotherapy versus letrozole plus abemaciclib, chosen randomly, as neoadjuvant therapy (deliver before breast cancer surgery), with positive Hormone Receptors (female hormones) and negative HER2 (protein involved in cell division that is located in the surface of many cells), intermediate/high risk breast cancer
    Estudio clínico para comparar eficacia y seguridad de la quimioterapia estándar frente a letrozol más abemaciclib, asignado al azar, como terapia neoadyuvante (administrada antes de la cirugía del tumor de mama), en pacientes con cáncer de mama con receptores hormonales (hormonas femeninas) positivos y HER2 (proteína involucrada en la división celular que se encuentra en la superficie de numerosas células) negativo, de riesgo alto/intermedio
    A.3.2Name or abbreviated title of the trial where available
    CARABELA
    CARABELA
    A.4.1Sponsor's protocol code numberGEICAM/2019-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04293393
    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 SponsorGEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLilly
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
    B.5.2Functional name of contact pointClinical Operations Department
    B.5.3 Address:
    B.5.3.1Street AddressAvenida de los Pirineos nº 7, 1ª Planta, oficina 1-14
    B.5.3.2Town/ citySan Sebastián de los Reyes (Madrid)
    B.5.3.3Post code28703
    B.5.3.4CountrySpain
    B.5.4Telephone number0034916592870
    B.5.5Fax number0034916510406
    B.5.6E-mailgeicam@geicam.org
    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 Yes
    D.2.1.1.1Trade name VERZENIOS
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form 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 INNABEMACICLIB
    D.3.9.1CAS number 1231929-97-7
    D.3.9.3Other descriptive nameABEMACICLIB
    D.3.9.4EV Substance CodeSUB171907
    D.3.10 Strength
    D.3.10.1Concentration unit Bq/mg becquerel(s)/milligram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    High/intermediate risk hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer patients with indication of neoadjuvant therapy
    Pacientes con cáncer de mama de riesgo alto/intermedio con receptores
    hormonales (RH) positivos / receptor del factor de crecimiento epidérmico humano 2 (HER2) negativo e indicación de terapia neoadyuvante
    E.1.1.1Medical condition in easily understood language
    Early Breast cancer with indication for neoadjuvant therapy (before surgery), with Hormone Receptors (female hormones) + and HER2 - (protein involved in cell division), intermediate/high risk
    Cáncer de mama precoz tratado con neoadyuvancia (antes de cirugía), con Receptores Hormonales (hormonas femeninas) + y HER2 (proteína involucrada en la división celular) -, riesgo intermedio/alto
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    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 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the Residual Cancer Burden (RCB) 0-I rate in both treatment arms
    Evaluar el porcentaje de Carga Tumoral Residual (RCB) 0-I en ambos brazos de tratamiento
    E.2.2Secondary objectives of the trial
    -Changes in Ki67 index value after 2 weeks of treatment in both treatment arms
    -RCB 0+I vs. RCB-II vs. RCB-III in both treatment arms (TNM downstaging)
    -Changes in RCB value between both treatment arms
    -Rate of PEPI score 0 at surgery in both treatment arms.
    -Clinical response measured by magnetic resonance imaging (MRI) according to RECIST v1.1 in both treatment arms
    -Rate of breast conserving surgery (BCS) in both treatment arms
    -iEFS (invasive Event Free Survival) in both treatment arms
    -Assessment of safety profile by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 classification
    -To assess molecular downstaging for high risk genomic groups defined by a multigene expression panel
    -Cambios en el valor del índice Ki67 después de 2 semanas de tratamiento en ambos brazos de tratamiento
    -RCB 0+I vs. RCB II vs. RCB III en ambos brazos de tratamiento (reducción del TNM)
    -Cambios en el valor del RCB entre ambos brazos de tratamiento
    -Porcentaje de puntuaciones PEPI igual a 0 en el momento de realizar la cirugía, en ambos brazos de tratamiento
    -Respuesta clínica mediante resonancia magnética (RM), determinada de acuerdo con los criterios RECIST v1.1, en ambos brazos de tratamiento
    -Porcentaje de cirugía conservadora de mama (BCS) en ambos brazos de tratamiento
    -Supervivencia libre de enfermedad invasiva (SLEi) en ambos brazos de tratamiento
    -Evaluación del perfil de seguridad mediante la versión 5.0 de la clasificación de los Criterios Terminológicos Comunes para los Acontecimientos Adversos (NCI-CTCAE)
    -Evaluar la reducción del estadio a nivel molecular en los grupos genómicos de alto riesgo, determinada mediante un panel de expresión de múltiples genes
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Generation of experimental biological models (organoids, xenographs, etc) to perform high-throughput functional screening studies and to identify relevant oncogenic drivers and treatment resistance mechanisms
    Generación de modelos experimentales (como xenoinjertos u organoides) para realizar estudios funcionales de alto rendimiento e identificar posibles percusores oncogénicos y mecanismos de resistencia
    E.3Principal inclusion criteria
    1.Written informed consent prior to any specific study procedures
    2.Women > or = 18 years of age
    3.Documentation of histologically confirmed primary invasive adenocarcinoma of the breast
    4.Availability of a primary tumor tissue sample obtained during the diagnostic process before treatment for the central assessment of Ki67 index
    5.Documentation of HR positive and HER2 negative BC based on local laboratory determination.
    a.HR positive is defined as more than or equal to 10% positive cells by IHC for ER and/or progesterone receptor (PgR)
    b.HER2 negative tumor is determined according to recommendations of ASCO/CAP 2018 guidelines
    6.Intermediate and high risk patients based on Ki67 index value (> or = 20%) determined at a central laboratory
    7.Patients should be in the following clinical stages of disease according to the 8th edition of the TNM Classification of Breast Cancer by the UICC (Union for International Cancer Control): T2 (> 2cm) – T3, T4b, N0 – N2, M0 (stages IIA, IIB, IIIA or IIIB). Subpopulation with tumors T2 N0 M0 will include high risk patients
    based on Ki67 index > 30% or Ki67 index between 20-30% and PgR negative with or without histological grade 3
    8.Patients diagnosed with multifocal or multicentric breast cancer will be eligible for the study if only 2 tumor lesions have been confirmed in the clinical evaluation and both lesions comply with the characteristics required by the protocol (please, refer to previous inclusion criteria)
    9.Indication of neoadjuvant treatment
    10.At the time of presentation, patients must be candidates for potentially curative surgery by surgeon’s assessment
    11.Sentinel lymph node biopsy (SLNB) will be preferable after the neoadjuvant treatment. Those patients with SLNB before the neoadjuvant treatment will be eligible for the study only if the SLNB has a negative result (N0). One Step Nucleic Acid Amplification (OSNA) method is not allowed
    12.Pre- and postmenopausal women.
    Postmenopausal status is defined as:
    -Patient underwent bilateral oophorectomy, or
    -Age > or = 60 years, or
    -Age < 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen or ovarian suppression) and Folliclestimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges.
    All women who do not meet the criteria for postmenopausal status are considered premenopausal for the purpose of this trial
    13.Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
    14.Patients are able to swallow oral medications
    15.Adequate organ and bone marrow function:
    ANC > or = 1,500/mm3 (1.5x109/L);
    -Platelets > ó = 100,000/mm3 (100x109/L)
    -Hemoglobin (Hgb) > or = 8g/dL (80g/L) (erythrocyte transfusions are permitted; initial treatment must not begin earlier than the day after the erythrocyte transfusion)
    -Total serum bilirubin < or = 1.5xULN (< or = 2xULN and direct bilirubin within normal limits if Gilbert´s disease)
    -AST and ALT < or = 3xULN
    16.Left ventricular ejection fraction (LVEF) > or = 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO)
    17.For premenopausal women: agreement to remain abstinent or use single or combined non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 3 weeks after the last dose of study treatment. Abstinence is only acceptable if it is in line with the preferred and
    usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide
    18.Negative serum pregnancy test within 7 days of the first dose of abemaciclib for premenopausal women, and for women who have experienced menopause onset < 12 months prior to first dose of therapy
    19.Patients consent to biological sample provision for biomarker exploratory analyses
    20.Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
    1.Consentimiento informado por escrito, obtenido previamente a la realización de cualquier procedimiento específico del estudio
    2.Mujeres > ó = 18 años
    3.Cáncer de mama invasivo primario confirmado histológicamente y documentado
    4.Disponibilidad de una muestra de tejido del tumor primario, obtenida durante el proceso de diagnóstico y antes de administrar el tratamiento, para poder evaluar el índice Ki67 de forma centralizada
    5.Documentación del CM RH-positivo/HER2-negativo, basándose en las determinaciones locales (del laboratorio del centro).
    a.RH-positivo se define como la presencia de > ó = 10% de células positivas para RE y/o RPg, determinadas por IHQ
    b.HER2-negativo se define de acuerdo con las recomendaciones de las guías de la ASCO/CAP 2018
    6.Pacientes con riesgo intermedio/alto, basándose en el valor del índice Ki67 (> ó = 20%) determinado en un laboratorio central
    7.Las pacientes deberán encontrarse en los siguientes estadios clínicos de la enfermedad, de acuerdo con la 8a edición de la clasificación TNM para el cáncer de mama de la UICC (unión internacional contra el cáncer, Union for International Cancer Control): T2 (> 2cm) – T3, T4b, N0 – N2, M0 (estadios IIA, IIB, IIIA o IIIB). La subpoblación con tumores T2 N0 M0 incluirá a pacientes de alto riesgo, determinado mediante un índice Ki67 > 30% o un índice Ki67 entre un 20% y un 30% y RPg negativo, con o sin un grado histológico de 3 8. Las pacientes diagnosticadas de cáncer de mama multifocal o multicéntrico serán elegibles para participar en el estudio si se han confirmado solamente dos lesiones tumorales en la evaluación clínica y ambas lesiones cumplen las características requeridas por el protocolo (consúltense los criterios de inclusión anteriores)
    9.Indicación de tratamiento NA
    10.En el momento de su diagnóstico las pacientes deben ser candidatas a cirugía con intención curativa, según la evaluación del cirujano
    11.Es preferible realizar la biopsia selectiva del ganglio centinela (BSGC) después del tratamiento NA. Las pacientes sometidas a BSGC antes de la terapia NA solamente serán elegibles para el estudio si la BSGC fue negativa (N0). No está permitido la realización del método OSNA, del inglés One Step Acid Amplification
    12.Mujeres pre- y posmenopáusicas.
    El estado posmenopáusico se define como:
    -Paciente sometida a ooforectomía bilateral, o
    -Edad > ó = 60 años, o bien
    -Edad < 60 años y amenorrea de 12 meses de duración o más (en ausencia de QT, tratamiento con tamoxifeno, toremifeno o supresión ovárica) y concentraciones plasmáticas de hormona foliculoestimulante (FSH) y estradiol en niveles posmenopáusicos, de acuerdo con los intervalos de normalidad de cada centro.
    Todas las mujeres que no cumplan los criterios de estado posmenopáusico se considerarán premenopáusicas a efectos de este ensayo.
    13.Pacientes con un estado funcional ECOG (Eastern Cooperative Oncology Group) de 0 ó 1
    14.Pacientes que puedan ingerir medicamentos por vía oral
    15.Pacientes con función orgánica y de la médula ósea adecuadas:
    -RAN (recuento absoluto de neutrófilos) > ó = 1.500/mm3 (1,5 x109/l);
    -Plaquetas > ó = 100.000/mm3 (100 x109/l);
    -Hemoglobina (Hb) > ó = 8 g/dl (80 g/l) (se permiten las transfusiones de hematíes; el tratamiento inicial no podrá empezar antes del día siguiente a la transfusión de hematíes);
    -Bilirrubina total sérica < ó = 1,5 x LSN (límite superior de la normalidad) (< ó = 2 x LSN y bilirrubina directa dentro de los límites de normalidad en presencia de enfermedad de Gilbert)
    -AST(aspartato aminotransferasa) y ALT (alanina aminotransferasa) < ó = 3 x LSN 16.Fracción de eyección del ventrículo izquierdo (FEVI) > ó = 50%, medida con ventriculografía isotópica (MUGA) o ecocardiografía (ECO)
    17.Mujeres premenopáusicas: deberán estar de acuerdo en mantener abstinencia de relaciones sexuales o usar métodos anticonceptivos no hormonales, únicos o combinados, que se asocien a una tasa anual de fracasos < 1% durante el periodo de tratamiento y durante 3 semanas como mínimo después de haber recibido la última dosis del tratamiento del estudio. La abstinencia sexual solo es aceptable si coincide con las preferencias de estilo de vida de la paciente y es su método habitual. La abstinencia periódica (p. ej., métodos del calendario, ovulación, sintotérmico o postovulación) y el coitus interruptus no son métodos anticonceptivos aceptables (consultar criterio completo en protocolo)
    18.Resultado negativo de la prueba de embarazo en suero dentro de los 7 días anteriores a la primera dosis de abemaciclib, en las mujeres premenopáusicas, y en las mujeres que hayan iniciado la menopausia con una anterioridad < 12 meses
    19.Consentimiento de la paciente para proporcionar muestras biológicas para los análisis exploratorios de biomarcadores
    20.Disposición y capacidad para cumplir con las visitas planificadas, el plan de tratamiento, los análisis de laboratorio y el resto de procedimientos del estudio
    E.4Principal exclusion criteria
    1.Previous anti-cancer treatment with therapeutic intent for current breast cancer is not allowed
    2.Inflammatory breast cancer, multifocal/multicentric breast cancer with > or = 3 tumor lesions or synchronous bilateral invasive breast cancers are not eligible
    3.Serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea)
    4.Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption
    5.Females who are pregnant or lactating
    6.Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required
    for enrollment
    7.Personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest
    8.Diagnosis of any other malignancy within 5 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix or colorectal
    9.Prior hematopoietic stem cell or bone marrow transplantation
    10.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
    1.No se permite el tratamiento antineoplásico previo con intención terapéutica para el cáncer de mama actual
    2.El cáncer de mama inflamatorio, el cáncer de mama multifocal/multicéntrico con > ó = 3 lesiones tumorales y los cánceres de mama invasivos bilaterales sincrónicos no son elegibles
    3.Patologías médicas graves y/o no controladas preexistentes que, a juicio del investigador, puedan impedir la participación de la paciente en el estudio (por ejemplo, enfermedad pulmonar intersticial, disnea en reposo importante o que requiera oxígenoterapia, insuficiencia renal grave [p. ej., aclaramiento de creatinina estimado < 30 ml/min], antecedentes de resección quirúrgica mayor que afecte al estómago o al intestino delgado, enfermedad de Crohn o colitis ulcerosa preexistentes o enfermedades crónicas preexistentes que provoquen diarrea > ó = Grado 2 en la situación basal)
    4.Pacientes con problemas hereditarios raros de intolerancia a la galactosa, deficiencia total de lactasa o malabsorción de la glucosa o la galactosa
    5.Mujeres embarazadas o en periodo de lactancia
    6.Infecciones bacterianas sistémicas activas (que requieran antibióticos intravenosos [IV] en el momento de iniciar el tratamiento del estudio), infecciones fúngicas o infecciones víricas detectables (como la positividad conocida al virus de la inmunodeficiencia humana o la hepatitis B o C activa conocida [por ejemplo, antígeno de superficie de la hepatitis B positivo]). Para la inclusión en el estudio no se requiere screening
    7.Antecedentes personales de cualquiera de las siguientes patologías: síncope de origen cardiovascular, arritmia ventricular de causa patológica (incluyendo, entre otras, la taquicardia ventricular y la fibrilación ventricular) o paro cardiaco súbito
    8.Diagnóstico de cualquier otra neoplasia maligna en los 5 años previos a la aleatorización, a excepción del cáncer de piel de células basales o de células escamosas, o el carcinoma in situ de cérvix o colorrectal, adecuadamente tratados
    9.Trasplante de precursores hematopoyéticos o de médula ósea previo
    10.Otro trastorno médico o psiquiátrico, agudo o crónico, o alteración de laboratorio importante que pueda incrementar el riesgo asociado a la participación en el estudio o a la administración del fármaco en investigación, o que pueda interferir con la interpretación de los resultados del estudio y que, según el criterio del investigador, haga que la paciente no sea adecuada para su inclusión en el estudio
    E.5 End points
    E.5.1Primary end point(s)
    Evaluation of the number of patients with a Residual Cancer Burden (RCB) 0-I index as a measure of efficacy. RCB[19] is a continuous variable derived from the primary tumor dimensions, cellularity of the tumor bed, and axillary nodal burden. It is estimated from routine pathological sections of the primary breast tumor site and the regional lymph nodes after the completion of NA therapy. The pathological variables include bidimensional diameters of the primary tumor bed, the proportion of primary tumor area containing invasive carcinoma, the number of positive lymph nodes, and the diameter of the largest nodal metastasis
    Evaluación del número de pacientes con un índice de RCB 0-I, como medida de la eficacia. El RCB[9] es una variable continua que se calcula a partir de las dimensiones del tumor primario, la celularidad del lecho tumoral y la afectación de los ganglios axilares. El cálculo se efectúa a partir de las secciones patológicas de rutina del primario tumor de mama y de los ganglios linfáticos regionales, una vez completada la terapia NA. Las variables anatomopatológicas incluyen los diámetros bidimensionales del lecho del tumor primario, la proporción del área del tumor primario que contiene carcinoma invasivo, el número de ganglios positivos y el diámetro de la metástasis ganglionar mayor
    E.5.1.1Timepoint(s) of evaluation of this end point
    After all surgeries are done
    Una vez realizadas todas las cirugías
    E.5.2Secondary end point(s)
    1.Percentage of decrease in the geometric mean of Ki67 index value after 2 weeks of treatment in both treatments arms.
    Number of patients with cell cycle arrest (Ki67 < 2.7%) after 2 weeks of treatment in both treatment arms
    2.RCB is classified in four classes based on the residual disease (RD):
    -RCB-0 defined as pathological complete response
    -RCB-I defined as minimal RD
    -RCB-II defined as moderate RD
    -RCB-III defined as extensive RD
    3.Variation of RCB value based on the RD between both treatment arms
    4.PEPI (Preoperative Endocrine Prognostic Index)[20] requires pathological stage (tumor size and nodal status), level of Ki67 protein and Allred ER score measured on the surgical specimen. PEPI score 0 includes pT1 or pT2, pN0, Ki67 < or = 2.7%, Allred score > 2
    5.Clinical Response Rate (CRR) is defined as the proportion of subjects with complete or partial radiographic response. Complete response (CR) and partial response (PR) definitions are assessed by MRI at baseline and prior to breast surgery, with or without regional lymph nodes surgery, and categorized according to percent reduction in tumor size
    6.Rate of breast conserving surgery (BCS): defined as the proportion of patients who achieved BCS between both treatment arms
    7.Invasive event free survival (iEFS): defined as time from randomization to progressive disease (PD) or invasive disease recurrence (local, regional, distant, or contralateral), or death from any cause. Invasive disease recurrence is defined as:
    -Ipsilateral invasive breast tumor recurrence (including second primary invasive breast cancer): an invasive breast cancer involving the same breast parenchyma as the original primary lesion
    -Ipsilateral regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, other regional lymph nodes, chest wall, and/or skin of the ipsilateral breast)
    -Distant recurrence (i.e., evidence of breast cancer in any anatomic siteoutside local and/or regional location and that has been either histologically confirmed or clinically diagnosed as recurrent invasive breast cancer)
    -Contralateral invasive breast cancer
    -Second primary invasive cancer of non-breast origin
    8.Safety will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). AEs grade will be defined by the NCI-CTCAE version 5.0. AEs terms will be coded according to MedDRA dictionary
    9.Gene expression data provided by a multigene expression panel in sequential tumor biopsies
    1.Porcentaje de reducción de la media geométrica del valor del índice Ki67 después de 2 semanas de tratamiento en ambos brazos de tratamiento.
    Número de pacientes con detención del ciclo celular (Ki67 < 2,7%) después de 2 semanas de tratamiento en ambos brazos de tratamiento
    2.RCB: se clasifica en cuatro categorías, basándose en la enfermedad residual (ER):
    -RCB-0, definida como respuesta completa patológica
    -RCB-I, definida como ER mínima
    -RCBR-II, definida como ER moderada
    -RCB-III, definida como ER extensa
    3.Variación del valor del RCB entre ambos brazos de tratamiento, basándose en la ER
    4.Puntuación PEPI (índice de pronóstico endocrino preoperatorio)20]; requiere disponer del estadio patológico (dimensiones del tumor y estado de los ganglios linfáticos), la concentración de proteína Ki67 y la puntuación de Allred del RE, determinada en la pieza quirúrgica. La puntuación PEPI de 0 incluye: T1p o T2p, N0p, Ki67 < ó = 2,7% y puntuación de Allred > 2
    5.La tasa de respuesta clínica (TRC) se define como el porcentaje de pacientes con respuesta radiológica completa o parcial. La presencia de respuesta completa (RC) y respuesta parcial (RP) se evalúan mediante RM en el momento basal y antes de la cirugía mamaria con o sin cirugía de los ganglios linfáticos regionales, y se categorizan de acuerdo con el porcentaje de reducción del tamaño del tumor
    6.La tasa de cirugía conservadora de mama (BCS) se define como el porcentaje de pacientes en las que se ha logrado realizar una conservación de la mama en ambos brazos de tratamiento
    7.Supervivencia libre de de enfermedad invasiva (SLEi): se define como el tiempo transcurrido desde la aleatorización hasta la PE o la recaída de la enfermedad invasiva (local, regional, a distancia o contralateral) o la muerte por cualquier causa
    La recaída de la enfermedad invasiva se define como:
    -Recaída homolateral del tumor mamario invasivo (incluye los segundos primarios de cáncer de mama invasivo): cáncer de mama invasivo que afecta al mismo parénquima mamario que la lesión primaria original
    -Recaída regional homolateral del tumor mamario invasivo (es decir, cáncer de mama invasivo en la axila, en otros ganglios linfáticos regionales, en la pared torácica y/o en la piel homolateral respecto a la mama)
    -Recaída a distancia (es decir, evidencia de cáncer de mama en cualquier localización anatómica fuera de la local o regional, que haya sido confirmada histológicamente o diagnosticada clínicamente como recaída del cáncer de mama invasivo)
    -Cáncer de mama invasivo contralateral
    -Segunda neoplasia maligna invasiva primaria de origen no mamario
    8.La seguridad se evaluará mediante pruebas clínicas y de laboratorio estándar (hemograma, bioquímica sérica). El grado de los AA se definirá según la versión 5.0 de los NCI-CTCAE. Los términos de los AA se codificarán de acuerdo con el diccionario MedDRA
    9.Datos de expresión génica, obtenidos de un conjunto (panel) de expresión de múltiples genes a partir de biopsias tumorales seriadas
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 2 weeks of treatment, after finishing treatment, after finishing surgery, during follow-up
    A las 2 semanas de tratamiento, tras finalizar el tratamiento, tras finalizar la cirugía, durante el seguimiento
    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 No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) 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 concerned27
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS, including follow-up.
    Última visita del último paciente, incluyendo el periodo de seguimiento
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years13
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years13
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 state159
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    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)
    None (standar treatment)
    Ninguno (tratamiento estándar)
    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 Decision2020-06-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-27
    P. End of Trial
    P.End of Trial StatusOngoing
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