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    Summary
    EudraCT Number:2013-004391-35
    Sponsor's Protocol Code Number:NSABP-FB7
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-12-24
    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 ConcernedItaly - Italian Medicines Agency
    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.
    Studio clinico randomizzato di fase II per la valutazione dei regimi di terapia neoadiuvante con Paclitaxel settimanale più Neratinib o Trastuzumab o Neratinib e Trastuzumab seguito da Doxorubicina e Ciclofosfamide con Trastuzumab postoperatorio in donne con tumore alla mammella HER2-positivo localmente avanzato.
    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.
    Studio clinico precedente all'intervento chirurgico per valutare i regimi di Paclitaxel settimanale più Neratinib o Trastuzumab o Neratinib e Trastuzumab seguito da Doxorubicina e Ciclofosfamide con Trastuzumab postoperatorio in donne con tumore alla mammella HER2-positivo localmente avanzato.
    A.3.2Name or abbreviated title of the trial where available
    NSABP FB-7 STUDY
    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 Biotechnology, 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 number14242486500
    B.5.5Fax number14242486501
    B.5.6E-mailClinicalTrials@pumabiotechnology.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 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.2.1.2Country 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 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
    tumore alla mammella HER2-positivo localmente avanzato
    E.1.1.1Medical condition in easily understood language
    Breast cancer which is spreading locally
    tumore alla mammella diffuso localmente
    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.
    L'obiettivo primario è quello di determinare il tasso di risposta patologica completa nella mammella e nei linfonodi ascellari per i pazienti con carcinoma mammario HER2-positivo, localmente avanzato, dopo la terapia neoadiuvante.
    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.
    Determinare il tasso di risposta patologica completa nella mammella di pazienti con tumore alla mammella localmente avanzato;
    ­Determinare il tasso di risposta clinica completa in pazienti con massa palpabile mammaria;
    Determinare l'­intervallo libero da recidiva di 2 anni
    ­Determinare la sopravvivenza globale di 2 anni
    Determinare la tossicità dei regimi 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 paziente deve avere acconsentito a partecipare e aver firmato e datato un appropriato modulo di consenso approvato da IRB/IEC per accedere allo studio, per l'eventuale acquisizione di campioni tumorali con procedura di agobiopsia prima della randomizzazione, e per la presentazione di campioni tumorali e sanguigni necessari agli studi scientifici correlati del trial FB-7.
    2. I pazienti devono essere di sesso femminile.
    3.L'età delle pazienti deve essere > = 18 anni.
    4.Lo status di performance ECOG deve essere pari a 0 o 1.
    5.Le pazienti devono avere la capacità di deglutire farmaci per via orale.
    6.La diagnosi di adenocarcinoma invasivo della mammella deve essere stata eseguita tramite agobiopsia o biopsia incisionale limitata.
    7.Sulle pazienti deve essere eseguita l'analisi ER del tumore primario prima della randomizzazione. Se l'analisi del recettore degli estrogeni (ER) è negativa, allora va eseguita l'analisi del recettore dei progesteroni. (Sono ammesse pazienti con tumori sia positivi sia negativi per il recettore degli ormoni).
    8.Il tumore alla mammella deve essere classificato come HER2-positivo prima della randomizzazione. Gli esami che utilizzano ibridazione in situ fluorescente (FISH) o ibridazione in situ cromogenica (CISH) necessitano di amplificazione genica. Gli esami che utilizzano IHC richiedono un alto punteggio di marcatura (3+).
    9.La stadiazione clinica, sulla base della valutazione tramite esame fisico, deve essere IIB, IIIA, IIIB o IIIC secondo AJCC:
    -cT2 e cN1;
    -cT3 e c N0 o cN1;
    -Qualsiasi cT e cN2 o cN3; o
    -cT4
    10.Il paziente deve avere una massa nella mammella o ascella la cui misura sia > = 2,0 cm accertata con esame fisico, a meno che la paziente non abbia carcinoma mammario infiammatorio, nel qual caso non è richiesta malattia misurabile tramite esame fisico.
    11.Al momento della randomizzazione, i valori ematici misurati entro le 4 settimane precedenti la randomizzazione devono soddisfare i seguenti criteri:
    -La conta dei neutrofili (ANC) deve essere > = 1200/mm3
    -La conta piastrinica deve essere > = 100.000/mm3
    -L'emoglobina deve essere > = 10 g/dL
    12.Devono essere soddisfatti i seguenti criteri come prova di un'adeguata funzionalità epatica tramite esame eseguito entro le 4 settimane prima della randomizzazione:
    -la bilirubina totale deve essere < = limite superiore della norma (ULN) per il laboratorio a meno che la paziente non abbia un'elevazione della bilirubina > = ULN a 1,5xULN a causa della malattia di Gilbert o sindrome simile che comporti una lenta coniugazione della bilirubina; e
    -la fosfatasi alcalina deve essere < = 2,5xULN per il laboratorio; e
    -L'aspartato aminotransferasi (AST) e l'alanina aminotransferasi (ALT) devono essere < = 1,5xULN per il laboratorio.
    13.Le pazienti con fosfatasi alcalina > ULN ma < = 2,5xULN sono ammissibili allo studio se l'imaging del fegato (tomografia computerizzata [CT], risonanza magnetica [RM], tomografia a emissione di positroni [PET], o scansione PET-CT) eseguita entro le 4 settimane prima della randomizzazione non rivela malattia metastatica e sono soddisfatti i requisiti di cui al punto 4.2.12.
    14.Le pazienti affette da dolore scheletrico inspiegabile o con fosfatasi alcalina che sia > ULN ma < = 2,5xULN sono ammissibili allo studio se una scintigrafia ossea, una PET-CT o PET eseguite entro le 4 settimane precedenti la randomizzazione non rivelano una malattia metastatica. Le pazienti con ritrovamenti sospetti sulla scintigrafia ossea o sulla scansione PET sono ammissibili una volta determinato che i ritrovamenti sospetti sono di natura benigna tramite radiografia, risonanza magnetica o biopsia.
    15.La creatinina sierica misurata entro le 4 settimane prima della randomizzazione deve essere < = 1,5xULN per il laboratorio.
    16.La valutazione FEVS con ecocardiogramma 2-D o scansione MUGA eseguita nei 90 giorni prima della randomizzazione deve essere > = 50%, a prescindere dall'LLN della struttura.
    Nota: Dal momento che la FEVS precedente l'ingresso serve come basale per il confronto delle successive valutazioni FEVS per determinare se la terapia mirata possa essere somministrata, è fondamentale che questo studio basale sia una valutazione accurata della FEVS della paziente. Se il basale FEVS è > = 70%, si sollecita il ricercatore a confermare la precisione del risultato FEVS iniziale e a valutare la necessità di ripetere lo studio se la precisione è incerta.
    17.Test di gravidanza negativo per β-gonadotropina corionica umana (hCG) per donne in pre-menopausa con capacità riproduttiva (quelle biologicamente in grado di avere figli) e per donne che hanno raggiunto la menopausa da meno di 12 mesi.
    18.Le donne in età fertile devono accettare di sottoporsi all'assunzione di un metodo molto efficace di contraccezione, come giudicato accettabile dal ricercatore, dal momento del consenso informato fino a 28 giorni dopo l'ultima dose di qualsiasi prodotto sperimentale.
    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.Aspirazione con ago sottile (FNA) come unica procedura per la diagnosi del tumore alla mammella primario
    2.Biopsia escissionale o nodulectomia prima della randomizzazione
    3.Procedura di stadiazione chirurgica dell'ascella prima della randomizzazione: le procedure autorizzate prima dell'ammissione includono:
    1) FNA o agobiopsia di un linfonodo ascellare per qualsiasi paziente e
    2) biopsia pre-terapia neoadiuvante del linfonodo sentinella (SN) per pazienti con linfonodi ascellari clinicamente negativi (non consigliato)
    4.Prova clinica o radiologica definitiva di malattia metastatica. L'imaging toracico, obbligatorio per tutte le pazienti, e le altre procedure di imaging, se richieste, vanno eseguite nei 90 giorni precedenti la randomizzazione
    5.Storia di tumore alla mammella invasivo ipsilaterale indipendentemente dal trattamento o carcinoma duttale in situ ipsilaterale (DCIS) trattato con radioterapia. Pazienti con una storia di carcinoma lobulare in situ (LCIS) sono ammissibili
    6.Tumore alla mammella invasivo controlaterale in qualsiasi momento. Pazienti con DCIS o LCIS controlaterale sono ammissibili
    7.Storia di tumori maligni che non interessano la mammella (fatta eccezione per i tumori in situ trattati solamente con escissione locale e carcinomi della pelle a cellule basali o squamose) nei 5 anni prima della randomizzazione
    8.Malattia metastatica diagnosticata dipendente da qualsiasi tumore maligno (solido o ematologico)
    9.Precedente terapia con antracicline, taxani, ciclofosfamide, trastuzumab o neratinib per qualsiasi tumore maligno
    10.Trattamento, incluse radioterapia, chemioterapia e/o terapia mirata, somministrato per il tumore della mammella attualmente diagnosticato prima della randomizzazione
    11.Terapia endocrina continuativa come raloxifene o tamoxifene (o altro SERM) o inibitore dell'aromatasi. Le pazienti sono ammesse se queste terapie farmacologiche sono interrotte prima della randomizzazione
    12.Qualsiasi terapia ormonale sessuale continuativa, i.e. pillola anticoncezionale e terapia ormonale sostitutiva ovarica. Le pazienti sono ammissibili se questi terapie farmacologiche sono interrotte prima della randomizzazione
    13.Epatite B attiva o C con anomalie nei test di funzionalità epatica
    14.Malattia polmonare intrinseca con conseguente dispnea
    15.Infezione attiva o infezione cronica che necessiti di trattamenti antibiotici soppressivi cronici
    16.Sindrome da malassorbimento, colite ulcerosa, malattia infiammatoria intestinale, resezione dello stomaco o dell'intestino tenue, o altra malattia o disturbo che colpisca in maniera significativa le funzioni gastrointestinali
    17.Diarrea > = di grado 2 persistente a prescindere dall'eziologia
    18.Neuropatia sensoriale o motoria > = di grado 2, come definito in CTCAE v3.0 del NCI
    19.Disturbi che impedirebbero la somministrazione intermittente di corticosteroidi per la premedicazione del paclitaxel
    20.Trattamento giornaliero cronico con corticosteroidi con dosaggio di > = 10 mg/die di metilprednisolone equivalente (esclusi steroidi per via inalatoria)
    21.Ipertensione non controllata definita come pressione sistolica > 150 mmHg o pressione diastolica > 90 mmHg, con o senza farmaci anti-ipertensivi. Le pazienti con ipertensione ben controllata con terapia farmacologica sono ammissibili
    22.Malattia cardiaca (storia e/o malattia attiva) che impedirebbe l'assunzione di un qualsiasi farmaco incluso nel regime di trattamento. Questo include, ma non è limitato a:
    Malattia cardiaca attiva:
    -angina pectoris sintomatica negli ultimi 180 giorni che abbia richiesto l'inizio o l'aumento di una terapia farmacologica antianginosa o altro intervento;
    -aritmie ventricolari, con eccezione per le contrazioni ventricolari premature benigne;
    -aritmie sopraventricolari e nodali che richiedano un pacemaker o che non siano controllate con farmaci;
    -anomalia di conduzione che richieda un pacemaker;
    -valvulopatia con compromissione documentata della funzione cardiaca; e
    -pericardite sintomatica;
    Storia di malattia cardiaca:
    -infarto miocardico documentato da enzimi cardiaci elevati o anomalie persistenti della parete regionale dopo valutazione della funzione ventricolare sinistra;
    -storia di insufficienza cardiaca congestizia documentata; e
    -cardiomiopatia documentata.
    23.Altre malattie sistemiche non maligne che impedirebbero alla paziente di ricevere il trattamento di studio o il follow-up necessario
    24.Gravidanza o allattamento al momento della randomizzazione: Il test di gravidanza deve essere effettuato entro 14 giorni prima della randomizzazione, documentato da test di hCG negativo per le donne in età fertile
    25.Il ricercatore deve esaminare la paziente per determinare se quest'ultima abbia qualche disturbo psichiatrico o dipendenza o altra condizione che, a suo giudizio, ne precluderebbero l'ammissibilità allo studio
    26.Utilizzo di qualsiasi farmaco sperimentale nelle 4 settimane prima della randomizzazione
    E.5 End points
    E.5.1Primary end point(s)
    Pathologic complete response rate (pCR) in breast and nodes.
    Tasso di risposta patologico completa nella mammella e nei linfonodi ascellari
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the time of surgery, approximately 7 months from randomization.
    Al momento dell'intervento chirurgico, a circa 7 mesi dalla randomizzazione.
    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).
    -Risposta patologica completa nella mammella;
    -Risposta clinica completa determinata da esame fisico al termine del trattamento
    con paclitaxel (prima di AC);
    -Risposta clinica completa determinata da esame fisico al completamento di AC (prima dell'intervento chirurgico);
    -Eventi per l'analisi dell'intervallo libero da recidiva includono la progressione della malattia inoperabile e recidiva locale, regionale e distante durante i 2 anni dalla randomizzazione;
    -Tempo dalla randomizzazione fino alla morte per qualsiasi causa;
    -Tossicità riportate, includendo cardiotossicità, come definito da Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0).
    E.5.2.1Timepoint(s) of evaluation of this end point
    2 years from randomization;
    Time from randomization until death from any cause.
    2 anni dalla randomizzazione;
    Tempo dalla randomizzazione fino alla morte per qualsiasi 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 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 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 concerned8
    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
    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: 63
    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 state12
    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
    Nessuno
    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 Decision2014-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-21
    P. End of Trial
    P.End of Trial StatusOngoing
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