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    Summary
    EudraCT Number:2013-004391-35
    Sponsor's Protocol Code Number:NSABP-FB7
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-01-10
    Trial results View 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 number2013-004391-35
    A.3Full title of the trial
    A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy Regimens with Weekly Paclitaxel plus Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast Cancer.
    Ensayo Clínico fase II, aleatorizado, para evaluar la eficacia del tratamiento neoadyuvante con Paclitaxel semanal más Neratinib o Trastuzumab o la combinación de Neratinib y Trastuzumab seguido de Doxorrubicina y Ciclofosfamida y de Trastuzumab postoperatorio en mujeres con cáncer de mama HER2-positivo localmente avanzado.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study before surgery evaluating Regimens with Weekly Paclitaxel plus Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast Cancer.
    A.3.2Name or abbreviated title of the trial where available
    NSABP FB-7 STUDY
    A.4.1Sponsor's protocol code numberNSABP-FB7
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01008150
    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 SponsorPuma Biotechnology 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 supportPuma Biotechnology, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPuma Biotechology, Inc.
    B.5.2Functional name of contact pointClinical Trials Information Desk
    B.5.3 Address:
    B.5.3.1Street Address10880 Wilshire Blvd, Suite 2150
    B.5.3.2Town/ cityLos Angeles
    B.5.3.3Post codeCA 90024
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34932214135
    B.5.5Fax number+34932992382
    B.5.6E-mailalicia.garcia@medsir.net
    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 nameNeratinib
    D.3.2Product code PB-272; HKI-272
    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 INNNeratinib
    D.3.9.1CAS number 698387-09-6
    D.3.9.3Other descriptive nameNERATINIB
    D.3.9.4EV Substance CodeSUB32232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Herceptin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for concentrate for solution for injection/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 INNTRASTUZUMAB
    D.3.9.1CAS number 180288-69-1
    D.3.9.4EV Substance CodeSUB12612MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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) No
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The 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 Concentrate for solution for injection/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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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
    Locally advanced HER2-positive breast cancer
    Cancer de mama HER2-positivo localmente avanzado
    E.1.1.1Medical condition in easily understood language
    Breast cancer which is spreading locally
    Cancer de mama localmente avanzado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10065430
    E.1.2Term HER-2 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 16.1
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the pathologic complete response rate in breast and axillary lymph nodes (pCR breast and nodes) for patients with HER2-positive locally advanced breast cancer (LABC) following neoadjuvant therapy.
    Determinar la tasa de respuesta patologica completa en mama y ganglios linfaticos axilares para pacientes con carcinoma de mama HER2-positivo localmente avanzado despues de la terapia neoadyuvante
    E.2.2Secondary objectives of the trial
    To determine the pathologic complete response (pCR) rate in breast in patients with locally advanced breast cancer (LABC);
    To determine the clinical complete response (cCR) rate in patients with LABC who present with palpable disease;
    To determine 2-year recurrence-free interval (RFI);
    To determine 2-year overall survival (OS);
    To determine toxicities of the FB-7 regimens.
    ­Para determinar lo siguiente:
    ­-tasa de respuesta patológica completa en mama
    ­-tasa de respuesta clínica completa
    ­-intervalo libre de recidiva a 2 años
    ­-supervivencia global a 2 años
    ­-toxicidades de los regímenes del FB-7
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The patient must have consented to participate and must have signed and dated an appropriate IRB/IEC-approved consent form to enter the study, for the optional procurement of tumor samples by a core biopsy procedure prior to randomization, and for submission of tumor and blood samples required for the FB-7 correlative science studies (see Section 7.1).
    2. Patients must be female.
    3. Patients must be > = 18 years old.
    4. The European Cooperative Oncology Group (ECOG) performance status must be 0 or 1.
    5. Patients must have the ability to swallow oral medication.
    6. The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy or by limited incisional biopsy.
    7. Patients must have estrogen receptor (ER) analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then progesterone receptor (PgR) analysis must also be performed. Patients are eligible with either hormone receptor-positive or hormone receptor-negative tumors.
    8. Breast cancer must be determined to be HER2-positive prior to randomization. Assays using FISH or CISH require gene amplification. Assays using IHC require a strongly positive (3+) staining score.
    9. Clinical staging, based on the assessment by physical exam, must be AJCC stage IIB, IIIA, IIIB, or IIIC:
    - cT2 and cN1;
    - cT3 and cN0 or cN1;
    - Any cT and cN2 or cN3; or
    - cT4.
    10. The patient must have a mass in the breast or axilla measuring > = 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in which case measurable disease by physical exam is not required.
    11. At the time of randomization, blood counts performed within 4 weeks prior to randomization must meet the following criteria:
    - Absolute neutrophil count (ANC) must be > = 1200/mm3;
    - Platelet count must be > = 100,000/mm3;
    - Hemoglobin must be > = 10 g/dL;
    12. The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to randomization must be met:
    - total bilirubin must be < = upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert' s disease or similar syndrome involving slow conjugation of bilirubin; and
    - alkaline phosphatase must be < = 2.5 x ULN for the lab; and
    - aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be < = 1.5 x ULN for the lab.
    13. Patients with alkaline phosphatase > ULN but < = 2.5 x ULN are eligible for inclusion in the study if liver imaging (Computerized Tomography [CT], Magnetic Resonance Imaging [MRI], Positron Emission Tomography [PET], or PET-CT scan) performed within 4 weeks prior to randomization does not demonstrate metastatic disease and the requirements in Section 4.2.12 are met.
    14. Patients with either unexplained skeletal pain or alkaline phosphatase that is > ULN but < = 2.5 x ULN are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 4 weeks prior to randomization does not demonstrate metastatic disease. Patients with suspicious findings on bone scan or PET scan are eligible if suspicious findings are determined to be benign by x-ray, MRI, or biopsy.
    15. Serum creatinine performed within 4 weeks prior to randomization must be < = 1.5 x ULN for the lab.
    16. The LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior to randomization must be > = 50% regardless of the facility's lower limit of normal (LLN). Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments to determine if targeted therapy can be administered, it is critical that this baseline study be an accurate assessment of the patient's LVEF. If the baseline LVEF is > = 70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and to consider repeating the study if the accuracy is uncertain.
    17. Negative b-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause.
    18. Women of child bearing potential (WOCBP) must agree and commit to use of a highly effective method of contraception, as determined to be acceptable by the investigator, from the time of informed consent until 28 days after the last dose of any investigational product.
    1.La paciente debe haber dado su consentimiento para participar y haber firmado y fechado el formulario de consentimiento informado aprobado por el CEIC para participar en el estudio, para la obtención opcional de muestras tumorales mediante un procedimiento de biopsia con aguja gruesa (core) antes de la aleatorización, y para el envío de las muestras del tumor y de sangre necesarias para llevar a cabo los estudios científicos correlativos
    2.Las pacientes deben ser mujeres
    3.Las pacientes deben tener > = 18 años de edad
    4.El estado funcional según ECOG debe ser 0 o 1
    5.Las pacientes deben poder tragar la medicación oral
    6.El diagnóstico de adenocarcinoma invasor de mama debe haber sido realizado mediante una biopsia con aguja gruesa (core) o biopsia incisional limitada
    7.Antes de la aleatorización, las pacientes deben haber realizado el análisis de RE en el tumor primario. Si el análisis de receptores de estrógenos (RE) es negativo, entonces también se debe realizar el análisis de receptores de progesterona (RP). (Las pacientes son elegibles ya sean tumores con receptores hormonales positivos o receptores hormonales negativos.)
    8.El cáncer de mama debe ser determinado como HER2-positivo antes de la aleatorización. Los ensayos que utilicen hibridación fluorescente in situ (FISH) o hibridación cromogénica in situ (CISH) requieren amplificación genética. Los ensayos con IHC requieren una puntuación de tinción altamente positiva (3 +)
    9.La estadificación clínica, basada en la evaluación mediante un examen físico, debe ser conforme a los estadios del AJCC, IIB, IIIA, IIIB o IIIC:
    -cT2 y cN1;
    -cT3 y cN0ocN1;
    -Cualquier cT ycN2 y cN3; o
    -cT4
    10.La paciente debe tener una masa en la mama o en la axila que mida> = 2,0 cm por examen físico, a menos que el paciente tenga cáncer de mama inflamatorio, en cuyo caso no se requiere enfermedad medible por examen físico
    11.En el momento de la asignación aleatoria, los hemogramas realizados en las 4 semanas previas a la aleatorización deben cumplir con los siguientes criterios:
    -Recuento absoluto de neutrófilos (RAN): > = 1200/mm3
    -Recuento de plaquetas: > = 100.000/mm3
    -Hemoglobina: > = 10 g/dl
    12.Para evidenciar una función hepática adecuada durante las 4 semanas previas a la aleatorización se han de cumplir los siguientes criterios:
    -bilirrubina total: < = límite superior de la normalidad (LSN) para el laboratorio a menos que el paciente tenga una incremento en la bilirrubina > LSN a 1,5 x LSN debido a la enfermedad de Gilbert o síndrome similar que implique una lenta conjugación de la bilirrubina; y
    -fosfatasa alcalina: < = 2,5 x LSN para el laboratorio; y
    -AST y ALT: < = 1,5 veces el límite superior de la normalidad (LSN) para el laboratorio
    13.Las pacientes con fosfatasa alcalina > LSN pero < = 2,5 x LSN son elegibles para su inclusión en el estudio si las imágenes del hígado (tomografía axial computarizada [TAC], resonancia magnética [RM], tomografía por emisión de positrones [PET], o PET/TAC) realizada durante las 4 semanas antes de la aleatorización no muestran la existencia de enfermedad metastásica y se cumplan los requisitos de la Sección 4.2.12
    14.Las pacientes con dolor esquelético sin explicación o fosfatasa alcalina que es > LSN pero < = 2,5 x LSN son elegibles para su inclusión en el estudio si la gammagrafía ósea, PET/TAC o PET realizado durante las 4 semanas previas a la aleatorización no muestra enfermedad metastásica. Las pacientes con hallazgos sospechosos en la gammagrafía ósea o PET son elegibles si los hallazgos sospechosos resultan ser benignos por rayos X, resonancia magnética, o biopsia
    15.La prueba de creatinina en suero realizada durante las 4 semanas antes de la aleatorización debe ser < = 1,5 x LSN para el laboratorio
    16.La evaluación de la FEVI por ecocardiografía 2-D o ventriculografía isotópica (MUGA) realizada durante los 90 días anteriores a la aleatorización debe ser > = 50%, independientemente del LIN de la instalación
    Nota: Dado que la FEVI previa a la entrada sirve como valor basal para comparar las evaluaciones posteriores de la FEVI para determinar si la terapia dirigida se puede administrar, es fundamental que este estudio de valor basal sea una evaluación precisa de la FEVI de la paciente. Si la valor basal de la FEVI es > = 70%, se recomienda que el investigador pida la confirmación del mismo y considere la posibilidad de repetir el estudio si el grado de precisión es incierto
    17.Prueba de embarazo de β (GCH) para las mujeres premenopáusicas en edad fértil (aquellas biológicamente capaces de tener hijos) y para las mujeres que comenzaron la menopausia hace menos de 12 meses
    18.Las mujeres en edad fértil deben estar de acuerdo y comprometerse con el uso de un método anticonceptivo altamente eficaz, de acuerdo con las indicaciones del investigador, desde el momento del consentimiento informado hasta 28 días después de la última dosis de cualquier producto en investigación.
    E.4Principal exclusion criteria
    1. Fine needle aspiration (FNA) alone to diagnose the primary breast cancer.
    2. Excisional biopsy or lumpectomy performed prior to randomization.
    3. Surgical axillary staging procedure prior to randomization. Procedures that are permitted prior to study entry include: 1) FNA or core biopsy of an axillary node for any patient, and 2) although not recommended, a pre-neoadjuvant therapy sentinel node (SN) biopsy for patients with clinically negative axillary nodes.
    4. Definitive clinical or radiologic evidence of metastatic disease. Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization.
    5. History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral ductal carcinoma in situ (DCIS) treated with radiation therapy (RT). Patients with a history of lobular carcinoma in situ (LCIS) are eligible.
    6. Contralateral invasive breast cancer at any time. Patients with contralateral DCIS or LCIS are eligible.
    7. History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization.
    8. Known metastatic disease from any malignancy (solid tumor or hematologic).
    9. Previous therapy with anthracyclines, taxanes, cyclophosphamide, trastuzumab, or neratinib for any malignancy.
    10. Treatment including RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to randomization.
    11. Continued endocrine therapy such as raloxifene or tamoxifen (or other selective estrogen receptor modulator [SERM]) or an aromatase inhibitor. Patients are eligible if these medications are discontinued prior to randomization.
    12. Any continued sex hormonal therapy, e.g., birth control pills and ovarian hormone replacement therapy. Patients are eligible if these medications are discontinued prior to randomization.
    13. Active hepatitis B or hepatitis C with abnormal liver function tests.
    14. Intrinsic lung disease resulting in dyspnea.
    15. Active infection or chronic infection requiring chronic suppressive antibiotics.
    16. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
    17. Persistent > = grade 2 diarrhea regardless of etiology.
    18. Sensory or motor neuropathy > = grade 2, as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0).
    19. Conditions that would prohibit intermittent administration of corticosteroids for paclitaxel premedication.
    20. Chronic daily treatment with corticosteroids with a dose of > = 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
    21. Uncontrolled hypertension defined as a systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg, with or without anti-hypertensive medications. Patients with hypertension that is well-controlled on medication are eligible.
    22. Cardiac disease (history of and/or active disease) that would preclude the use of any of the drugs included in the treatment regimen. This includes but is not confined to:
    Active cardiac disease:
    - symptomatic angina pectoris within the past 180 days that required the initiation of or increase in anti-anginal medication or other intervention;
    - ventricular arrhythmias except for benign premature ventricular contractions;
    - supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
    - conduction abnormality requiring a pacemaker;
    - valvular disease with documented compromise in cardiac function; and
    - symptomatic pericarditis.
    History of cardiac disease:
    - myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular function;
    - history of documented congestive heart failure (CHF); and
    - documented cardiomyopathy.
    23. Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.
    24. Pregnancy or lactation at the time of randomization. Pregnancy testing should be performed within 14 days prior to randomization documented by negative serum hCG test for women of child bearing potential.
    25. The investigator should assess the patient to determine if she has any psychiatric or addictive disorder or other condition that, in the opinion of the investigator, would preclude her from meeting the study requirements.
    26. Use of any investigational agent within 4 weeks prior to randomization.
    1.Solamente punción-aspiración con aguja fina (PAAF) para diagnosticar el cáncer de mama primario
    2.Biopsia por resección o lumpectomía realizada antes de la aleatorización
    3.Procedimiento quirúrgico de estadificación axilar antes de la aleatorización. Procedimientos permitidos antes del ingreso al estudio incluyen: 1) PAAF o biopsia con aguja gruesa (core) de un ganglio axilar para cualquier paciente, 2) aunque no es recomendable, biopsia previa terapia neoadyuvante del ganglio centinela (GC) en pacientes con ganglios axilares clínicamente negativos
    4.Evidencia clínica o radiológica definitiva de enfermedad metastásica. (Nota: Imágenes de diagnóstico del tórax (obligatorias para todas las pacientes) y otras imágenes [si es necesario] se deben haber obtenido durante los 90 días previos aleatorización)
    5.Antecedentes de cáncer de mama ipsilateral invasivo independientemente del tratamiento o CDIS ipsilateral tratados con RT (pacientes con antecedentes de CLIS son elegibles)
    6.Cáncer de mama contralateral invasivo, en cualquier momento. (pacientes con CDIS o CLIS contralateral son elegibles)
    7.Antecedentes de neoplasias no asociadas al cáncer de mama (con excepción de cánceres in situ tratados únicamente mediante resección local y carcinomas de piel de células basales y células escamosas) en los 5 años anteriores la aleatorización
    8.Enfermedad metastásica conocida derivada de cualquier neoplasia (tumor sólido o hematológico)
    9.Terapia previa con antraciclinas, taxanos, ciclofosfamida, trastuzumab, neratinib para cualquier neoplasia
    10.Tratamiento que haya incluido RT, quimioterapia, y/o terapia dirigida, administrada para cáncer de mama actualmente diagnosticado antes de la aleatorización
    11.Terapia continua endocrina como el raloxifeno o tamoxifeno (u otro MSRE) o un inhibidor de la aromatasa. Pacientes son elegibles si estos medicamentos se interrumpen antes de la aleatorización
    12. Cualquier terapia hormonal continua, i.e, pastillas anticonceptivas y terapia de reemplazo hormonal ovárica. Pacientes son elegibles si estos medicamentos se interrumpen antes de la aleatorización.
    13.Hepatitis B o hepatitis C activa con pruebas de función hepática anormales
    14.Enfermedad pulmonar intrínseca con dispnea resultante
    15.Infección activa o infección crónica que requiere tratamiento prolongado con antibióticos supresivos
    16.Síndrome de mala absorción, colitis ulcerosa, enfermedad inflamatoria del intestino, resección del estómago o intestino delgado, u otra enfermedad o condición que afecte significativamente la función gastrointestinal
    17.Diarrea persistente > = de grado 2, independientemente de la etiología
    18.Neuropatía sensorial o motoria > = de grado 2, según lo definido por el NCI CTCAE v3.0
    19.Afecciones que contra indiquen la administración intermitente de corticosteroides para premedicación de paclitaxel
    20.Tratamiento crónico diario con corticoides equivalente a una dosis de > = 10 mg/día de metilprednisolona (excluyendo esteroides inhalados)
    21.Hipertensión no controlada, definida como una presión arterial sistólica (PA) > 150 mmHg o diastolica > 90 mmHg, con o sin medicamentos antihipertensivos (Son elegibles pacientes con hipertensión que esté adecuadamente controlada con medicación)
    22.Enfermedad cardiaca (historia de y/o enfermedad activa) que podrían impedir el uso de cualquiera de los fármacos incluidos en el régimen de tratamiento. Esto incluye pero no se limita a:
    Enfermedad cardiaca activa:
    -angina de pecho sintomática en los últimos 180 días que requirió inicio o aumento de medicación antianginanosa u otra intervención;
    -arritmias ventriculares, excepto para contracciones ventriculares prematuras benignas;
    -arritmia supra ventricular y taquicardia nodal que requieren un marcapasos o que no están controladas con medicación;
    -alteración de la conducción cardiaca con necesidad de un marcapasos;
    -enfermedad valvular con afectación documentada de la función cardíaca, y
    -pericarditis sintomática.
    Antecedentes de enfermedad cardiaca:
    -infarto de miocardio documentado por elevación de enzimas cardíacas o anomalías persistentes en pared regional basadas en evaluación de la función ventricular izquierda;
    -antecedentes de insuficiencia cardiaca congestiva documentada (ICC); y
    -cardiomiopatía documentada.
    23.Otra enfermedad sistémica no maligna que descartara a la paciente a recibir el tratamiento del estudio o impidiese el seguimiento requerido.
    24.Embarazo o lactancia en el momento de la aleatorización. (Nota: pruebas de embarazo se deben realizar durante 14 días anteriores a la aleatorización y han de documentarse mediante resultado negativo a la prueba del GCH para mujeres en edad fértil)
    25.Investigador debe evaluar la paciente para determinar si tiene algún trastorno psiquiátrico o adictivo u otra condición que, en su opinión, impediría cumplir con los requisitos del estudio
    26.Cualquier fármaco en investigación durante 4 semanas previas aleatorización
    E.5 End points
    E.5.1Primary end point(s)
    Pathologic complete response rate (pCR) in breast and nodes.
    Respuesta patologica completa en mama y ganglios
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the time of surgery, approximately 7 months from randomization.
    En el momento de la cirugia, aproximadamente 7 meses desde la aleatorizacion.
    E.5.2Secondary end point(s)
    Pathologic complete response (pCR) in breast;
    Clinical complete response (cCR) assessed by physical exam at the completion of paclitaxel (before AC);
    cCR assessed by physical exam at the completion of AC (before surgery);
    Events for analysis of recurrence-free interval (RFI) include inoperable progressive disease and local, regional, and distant recurrence during the 2 years from randomization;
    Time from randomization until death from any cause;
    Reported toxicities, including cardiotoxicity, as defined by Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0).
    La respuesta patologica completa (PCR) en mama;
    Respuesta clinica completa (RCC) evaluada por examen fisico al final de paclitaxel (antes AC);
    RpC evaluada por examen fisico en la terminacion de AC (antes de la cirugia);
    Acontecimientos para el analisis del intervalo libre de recidiva (RFI) incluyen enfermedad progresiva inoperable y recurrencia local, regional y distante durante los 2 anos a partir de la aleatorizacion;
    Tiempo desde la aleatorizacion hasta la muerte por qualquier causa;
    Toxicidades notificadas, incluyendo la cardiotoxicidad, segun la definicion de CTCAE v. 3.0.
    E.5.2.1Timepoint(s) of evaluation of this end point
    2 years from randomization;
    Time from randomization until death from any cause.
    2 anos a partir de la aleatorizacion;
    Tiempo desde la aleatorizacion hasta la muerte por cualquier causa.
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind 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 trial3
    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 concerned22
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    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
    Canada
    France
    Italy
    Portugal
    Spain
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    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: 63
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state33
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 56
    F.4.2.2In the whole clinical trial 126
    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
    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 Decision2014-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-11-25
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