Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   36827   clinical trials with a EudraCT protocol, of which   6080   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2017-004869-27
    Sponsor's Protocol Code Number:MK-3475-756
    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:2018-06-27
    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 number2017-004869-27
    A.3Full title of the trial
    A Randomized, Double-Blind, Phase III Study of Pembrolizumab versus Placebo in Combination with Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy for the Treatment of High-Risk Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2–) Breast Cancer (KEYNOTE-756)
    Estudio de fase III, aleatorizado y doble ciego de pembrolizumab en comparación con placebo en combinación con quimioterapia neoadyuvante y endocrinoterapia adyuvante en el tratamiento del cáncer de mama con receptores estrogénicos positivos y receptor tipo 2 del factor de crecimiento epidérmico humano negativo (RE+/HER2-) en estadio inicial de alto riesgo (KEYNOTE-756).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Trial for Newly Diagnosed High Risk ER+/HER2– (Estrogen Receptor Positive/ Human Epidermal growth factor receptor Negative) Breast Cancer
    Ensayo clínico de cáncer de mama recién diagnosticado con receptores estrogénicos positivos y receptor tipo 2 del factor de crecimiento epidérmico humano negativo (RE+/HER2-) en estadio inicial de alto riesgo.
    A.3.2Name or abbreviated title of the trial where available
    Phase III study of pembrolizumab for high-risk early-stage ER+/HER2– breast cancer
    Estudio de fase III de pembrolizumab en el cáncer de mama RE+/HER2- en estadio inicial de alto riesg
    A.4.1Sponsor's protocol code numberMK-3475-756
    A.5.4Other Identifiers
    Name:IND numberNumber:124 442
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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 supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme de España S.A.
    B.5.2Functional name of contact pointInvestigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressCalle Josefa Valcárcel, 38
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913210600
    B.5.5Fax number+34913210590
    B.5.6E-mailensayos_clinicos@merck.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 namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    High-Risk Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2–) Breast Cancer
    Cáncer de mama con receptores estrogénicos positivos y receptor tipo 2 del factor de crecimiento epidérmico humano negativo (RE+/HER2-) en estadio inicial de alto riesgo.
    E.1.1.1Medical condition in easily understood language
    newly diagnosed high risk ER+/HER2– breast cancer
    Cáncer de mama RE+/HER2- en estadio inicial, de alto riesgo, recién diagnosticado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    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 compare the rate of pathological complete response (pCR) at the time of definitive surgery, using the definition of ypT0/Tis ypN0 as assessed by the local pathologist, of pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.

    To compare event-free survival (EFS) following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator.
    Comparar la tasa de RCp en el momento de la cirugía definitiva, utilizando la definición de ypT0 ypN0, según la evaluación del patólogo local, entre pembrolizumab y placebo, ambos en combinación con los tratamientos antineoplásicos neoadyuvantes especificados en el protocolo.

    Comparar la supervivencia sin episodios (SSE) tras la administración de pembrolizumab y placebo, ambos en combinación con los tratamientos antineoplásicos neoadyuvantes y adyuvantes especificados en el protocolo, según lo determinado por el investigador.
    E.2.2Secondary objectives of the trial
    1.To compare:
    -OS following administration of pembrolizumab and placebo, both in combination with the neoadjuvant and adjuvant therapies
    -rate of pCR at definitive surgery, using ypT0 ypN0 and ypT0/Tis as assessed by local pathologist, of pembrolizumab vs placebo, both in combination with neoadjuvant therapies
    -rate of pCR at definitive surgery, using ypT0/Tis ypN0, ypT0 ypN0, and ypT0/Tis as assessed by local pathologist, of pembrolizumab vs placebo, both in combination with neoadjuvant therapies in sbj with PD-L1+ tumors (CPS ≥1)
    -EFS as determined by investigator and OS following administration of pembrolizumab and placebo, both in combination with neoadjuvant and adjuvant therapies, in sbj with PD-L1+ tumors (CPS ≥1)

    Read in the protocol
    1. Comparar:
    - La SG tras la administración de pembrolizumab y placebo, ambos en combinación con los tratamientos antineoplásicos neoadyuvantes y adyuvantes especificados en el protocolo.
    - La tasa de RCp en el momento de la cirugía definitiva, utilizando la definición de ypT0 ypN0, y ypT0/Tis según la evaluación del patólogo local, entre pembrolizumab y placebo, ambos en combinación con los tratamientos antineoplásicos neoadyuvantes especificados en el protocolo.
    - La tasa de RCp en el momento de la cirugía definitiva, utilizando tres definiciones (ypT0/Tis ypN0, ypT0 ypN0 y ypT0/Tis), según la evaluación del patólogo local, entre pembrolizumab y placebo, ambos en combinación con los tratamientos antineoplásicos neoadyuvantes especificados en el protocolo, en participantes con tumores con PD-L1 positivo (puntuación positiva combinada [PPC] ≥ 1).

    Read in the protocol
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1.Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.

    2.Magnetic resonance imaging of the breast will be performed in approximately 150 participants with high-risk early-stage ER+/HER2– breast cancer who choose to participate for more accurate clinical staging of the primary tumor and axilla lymphadenopathy and to ensure the primary tumor and regional lymph node staging fulfil protocol-required criteria.
    If a participant has consented to participating in the breast MRI, an MRI should be scheduled for 2 time points:
    • At Screening (prior to first dose of study treatment)
    • After completion of the neoadjuvant period (before definitive surgery)
    Changes in the MRI from the baseline will be assessed by the investigator per RECIST 1.1 Magnetic resonance imaging images of the breast will be sent to a designated central imaging vendor for collection, quality review, and independent imaging review.
    1. Merck realizará investigaciones biomédicas futuras con las muestras obtenidas para tal finalidad durante este ensayo clínico. Estas investigaciones tendrán por objeto el análisis de biomarcadores con el
    fin de abordar aspectos nuevos que no se describen en otras partes del protocolo (como parte del ensayo principal) y solo se llevarán a cabo en muestras de los pacientes que hayan otorgado el consentimiento
    correspondiente. El objetivo de la obtención de muestras para investigaciones biomédicas futuras es estudiar e identificar biomarcadores que proporcionen información a los científicos sobre las enfermedades y sus tratamientos. El objetivo último es utilizar tal
    información para desarrollar fármacos más seguros y eficaces o para garantizar que los sujetos reciban la dosis correcta del fármaco en elmomento preciso.

    2. Se realizarán resonancias magnéticas de mama en aproximadamente 150 participantes con cáncer de mama RE+/HER2- en estadio inicial, de alto riesgo, que elijan participar para una estadificación clínica más precisa del tumor primario y de linfadenopatía de axila y para asegurar que el tumor primario y la estadificación de los ganglios linfáticos regionales cumplen los criterios requeridos por el protocolo.
    Si un participante ha dado su consentimiento para participar en la resonancia magnética de mama, se le debe programar la resonancia en 2 puntos del estudio:
    • En el screening (antes de la primera dosis del tratamiento del estudio)
    • Después de completar el período neoadyuvante (antes de la cirugía definitiva)
    El investigador evaluará por RECIST 1.1 los cambios en las resonancias desde la resonancia de base. Las resonancias magnéticas de mama se enviarán a un proveedor de imágenes central designado para su recolección, revisión de calidad y revisión de imágenes independiente
    E.3Principal inclusion criteria
    Type of Participant and Disease Characteristics
    1. Participant has a localized invasive breast ductal adenocarcinoma, confirmed by the local pathologist, that includes either T1c-T2 (tumor size ≥2 cm), clinical node stage (cN)1-cN2, or T3-T4, cN0-cN2.
    2. Has centrally confirmed ER+/HER2–, breast cancer of ductal histology, according to the most recent American Society of Clinical Oncology/College of American Pathologist guidelines.
    3. Provides a new or recently obtained core needle biopsy, consisting of multiple cores, taken from the primary breast tumor(s) for central determination of HR status (ER and progesterone receptor), HER2, and PD-L1 status.
    Demographics
    4. Is a male or female ≥18 years of age on the day of signing informed consent.
    5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to initiation of study treatment
    Male participants:
    6. A male participant must agree to use a contraception as detailed in Appendix 3 of the protocol during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment and refrain from donating sperm during this period.
    Female participants:
    7. A female participant is eligible to participate if she is not pregnant , not breastfeeding, and at least one of the following conditions applies:
    a.) Not a woman of childbearing potential (WOCBP)
    OR
    b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment with pembrolizumab or placebo.
    Informed Consent
    8. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However the participant may participate in the main study without participating in future biomedical research.
    Laboratory Evaluations
    9. Has adequate organ function, as detailed in the protocol; all screening laboratory tests should be performed within 10 days prior to initiation of study treatment.
    Tipo de participante y características de la enfermedad
    1. Presencia de un adenocarcinoma canalicular de mama invasivo localizado, confirmado por el patólogo local, que incluye T1c-T2 (tamaño del tumor ≥ 2 cm), estadio ganglionar clínico (cN)1-cN2 o T3-T4, cN0-cN2.
    2. Cáncer de mama RE+/HER2- con confirmación centralizada, histología canalicular, según las directrices más recientes de la American Society of Clinical Oncology/College of American Pathologist.
    3. Donación de una biopsia con aguja gruesa nueva u obtenida recientemente, constituida por varios cilindros, del tumor de mama primario para una determinación centralizada de la expresión de RH (RE y receptores de progesterona), HER2 y PD-L1.
    Datos demográficos
    4. Participante de uno u otro sexo con una edad mínima de 18 años el día de la firma del consentimiento informado.
    5. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1, evaluado en los 10 días previos al inicio del tratamiento del estudio
    Varones:
    6. Los varones deben comprometerse a utilizar métodos anticonceptivos tal como se detalla en el apéndice 3 de este protocolo durante el período de tratamiento y hasta, como mínimo, 12 meses (en los participantes que reciban ciclofosfamida) o 6 meses (en los que no reciban ciclofosfamida) después de la última dosis del tratamiento del estudio, así como a abstenerse de donar semen durante este período.
    Mujeres:
    7. Una mujer podrá participar en el estudio si no está embarazada (véase el apéndice 3), no está amamantando y cumple al menos una de las condiciones siguientes:
    a.) No es una mujer en edad fértil (MEF), según se define en el apéndice 3
    O
    b. ) Es una MEF que se compromete a seguir las normas sobre anticonceptivos recogidas en el apéndice 3 durante el período de tratamiento y hasta, como mínimo, 12 meses (en los participantes que reciban ciclofosfamida) o 6 meses (en los que no reciban ciclofosfamida) después de la última dosis del tratamiento del estudio con pembrolizumab o placebo.
    Consentimiento informado
    8. El participante (o su representante legal cuando proceda) otorga su consentimiento informado por escrito para el estudio. El participante también podrá otorgar su consentimiento para las investigaciones biomédicas futuras. No obstante, el participante podrá participar en el estudio principal sin necesidad de hacerlo en las investigaciones biomédicas futuras.
    Evaluaciones analíticas
    9. Presencia de una función orgánica adecuada, tal como se detalla en la Tabla 2; todas las pruebas analíticas de selección deberán realizarse en los 10 días previos al inicio del tratamiento del estudio.
    E.4Principal exclusion criteria
    Medical Conditions
    1. Has a history of non-infectious pneumonitis that required treatment with steroids or has current pneumonitis.
    2. Has breast cancer with lobular histology.
    3. Has bilateral invasive breast cancer.
    4. Has metastatic (Stage IV) breast cancer.
    5. Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants of the breast).
    6. Has any of the following clinical lymph node staging per current AJCC staging criteria for breast cancer staging based on radiological and/or clinical assessment: cN3, cN3a, cN3b, or cN3c.
    7. Has ER–, progesterone receptor positive breast cancer.
    8. Participants who have undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or have undergone sentinel lymph node biopsy prior to study treatment.
    9. Has a known additional, invasive, malignancy that is progressing or required active treatment in the last 5 years.
    10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
    11. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs)
    12. Has a known history of active tuberculosis (Bacillus tuberculosis).
    13. Has an active infection requiring systemic therapy.
    14. Has a history or current evidence of any condition (eg, transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that is specifically contraindicated per the current locally-approved labeling, that might confound the results of the trial, interfere with the participant’s involvement for the full duration of the trial, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator.
    15. Has known psychiatric or substance abuse disorders that would may interfere with cooperation with the requirements of the trial.
    16. Has left ventricular ejection fraction (LVEF) of <50% or below the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
    17. Has other significant cardiac disease, such as:
    - History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months;
    - Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.
    18. Has a known history of human immunodeficiency virus (HIV) infection.
    19. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
    20. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Prior/Concomitant Therapy
    21. Has received prior treatment for breast cancer.
    22. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
    23. Has received a live vaccine within 30 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), typhoid, and intranasal influenza vaccines (eg, FluMist®) vaccine.
    24. Has severe hypersensitivity (≥Grade 3) to any of the components or excipients used in the study treatments.
    Prior/Concurrent Clinical Study Experience
    25. Is/was enrolled in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks (12 months for an investigational agent or device with anticancer or antiproliferative properties) prior to the first dose of study treatment.
    Other Exclusions

    Read in the protocol
    1. Antecedentes de neumonitis (no infecciosa) que precisó tratamiento con esteroides o presencia de una neumonitis activa.
    2. Cáncer de mama de histología lobulillar.
    3. Cáncer de mama invasivo bilateral.
    4. Cáncer de mama metastásico (estadio IV).
    5. Cáncer de mama multicéntrico (presencia de más de un tumor en diferentes cuadrantes de la mama).
    6. Presencia de alguno de los siguientes estadios ganglionares clínicos según los actuales criterios del AJCC para la estadificación del cáncer de mama basados en una evaluación radiológica o clínica: cN3, cN3a, cN3b o cN3c.
    7. Cáncer de mama con RE- y receptores de progesterona positivos.
    8. Participantes que se hayan sometido a una biopsia por escisión del tumor primario y/o de los ganglios linfáticos axilares o a una biopsia del ganglio centinela antes del tratamiento del estudio.
    9. Presencia de otra neoplasia maligna invasiva conocida que está en progresión o que ha necesitado tratamiento activo en los últimos 5 años.
    10. Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico con esteroides (en dosis superiores a 10 mg diarios de un equivalente de prednisona) o cualquier otra forma de tratamiento inmunodepresor en los siete días previos a la primera dosis del tratamiento del estudio.
    11. Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico (es decir, fármacos modificadores de la enfermedad, corticoides o inmunodepresores) en los dos últimos años.
    12. Antecedentes de tuberculosis activa (Bacillus tuberculosis).
    13. Infección activa con necesidad de tratamiento sistémico.
    14. Antecedentes o datos presentes de cualquier proceso (por ejemplo, anemia o trombocitopenia dependiente de transfusiones), tratamiento o anomalía analítica que suponga una contraindicación específica según la ficha técnica local vigente y que, en opinión del investigador responsable del tratamiento, podría confundir los resultados del ensayo, dificultar la participación durante la totalidad del ensayo o motivar que la participación no sea lo más conveniente para el participante.
    15. Presencia de un trastorno psiquiátrico o por abuso de sustancias que pueda dificultar el cumplimiento de los requisitos del ensayo.
    16. Fracción de eyección del ventrículo izquierdo (FEVI) ≥ 50 % o por debajo del límite inferior de la normalidad (LIN) del centro, evaluada mediante un ecocardiograma o ventriculografía isotópica en equilibrio (MUGA) realizado en la selección.
    17. Presencia de una cardiopatía importante, como:
    - Antecedentes de infarto de miocardio, síndrome coronario agudo o angioplastia, colocación de endoprótesis o injerto de derivación coronaria en los 6 últimos meses.
    - Insuficiencia cardíaca congestiva (ICC) en clase II-IV según la New York Heart Association (NYHA) o antecedentes de ICC en clase III o IV según la NYHA.
    18. Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH).
    19. Antecedentes de infección por el virus de la hepatitis B (reactividad del antígeno de superficie del virus de la hepatitis B [HBsAg]) o de infección activa por el virus de la hepatitis C (definida como detección de ARN del virus de la hepatitis C [VHC] [cualitativo]).
    20. Mujer en edad fértil que da positivo en una prueba de embarazo en orina realizada en las 72 horas previas a la primera dosis del tratamiento del estudio (véase el apéndice 3). Cuando el resultado de la prueba en orina no pueda confirmarse que es negativo, será necesario hacer una prueba de embarazo en suero. En tal caso, la participante será excluida si el resultado de la prueba de embarazo en suero es positivo.
    21. Recepción de un tratamiento previo contra el cáncer de mama.
    22. Recepción de un tratamiento previo con un fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un fármaco dirigido contra otro receptor de los linfocitos T estimulador o coinhibidor (como CTLA-4, OX-40 o CD137).
    23. Recepción de una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis del tratamiento del estudio. Algunos ejemplos de vacunas de microorganismos vivos son, entre otros, los siguientes: vacuna contra el sarampión, antiparotídica, antirrubeólica, contra la varicela, contra la fiebre amarilla, antirrábica, bacilo de Calmette-Guérin (BCG), antitifoidea y vacunas antigripales intranasales (por ejemplo, FluMist®).
    24. Hipersensibilidad grave (grado > 3) a cualquiera de los componentes o excipientes utilizados en los tratamientos del estudio.
    25. Participación activa o pasada en un estudio de un fármaco en investigación y recepción del tratamiento del estudio o uso de un dispositivo en investigación en las 4 semanas (12 meses para un fármaco o dispositivo en investigación con propiedades antineoplásicas o antiproliferativas) previas a la primera dosis del tratamiento del estudio.

    Leer en el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    Pathological Complete Response Rate (ypT0/Tis ypN0)
    Event-Free Survival
    Tasa de respuesta completa patológica (ypT0 / Tis ypN0)
    Supervivencia sin episodios.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After Definitive Surgery and at any point PD/recurrance occur
    Después de la cirugía definitiva y en cualquier momento de progresión de enfermedad / recurrencia
    E.5.2Secondary end point(s)
    Overall Survival
    Pathological Complete Response Rate (ypT0 ypN0)
    Supervivencia global
    Tasa de respuesta patológica completa (ypT0 ypN0)
    E.5.2.1Timepoint(s) of evaluation of this end point
    After Definitive Surgery and at any point PD/recurrance occur
    Después de la cirugía definitiva y en cualquier momento de progresión de enfermedad / recurrencia
    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 No
    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) 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo 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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA111
    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
    Belgium
    Brazil
    Canada
    Colombia
    France
    Germany
    Hungary
    Ireland
    Israel
    Japan
    Korea, Republic of
    New Zealand
    Poland
    Portugal
    Russian Federation
    Spain
    Taiwan
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years12
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years12
    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: 855
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 285
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state75
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 585
    F.4.2.2In the whole clinical trial 1140
    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)
    After subjects have completed the adjuvant treatment phase, he/she will enter into a long term follow up phase. These Long Term Follow Up visits will be in-office visits with required assessments at protocol-specified timepoints. Any scans to assess disease recurrence are performed per local/institutional standard of care.
    Una vez de que los pacientes han completado la fase de tratamiento adyuvante, entrará en una fase de seguimiento a largo plazo. En este seguimiento a largo plazo las visitas se realizarán de manera presencial en el centro, con las evaluaciones requeridas por protocolo para cada punto de tiempo. Cualquier imagen para evaluar la recurrencia de la enfermedad será realizada según el estándar de atención local / institucional.
    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 Decision2018-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-07
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA