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    Summary
    EudraCT Number:2016-002676-27
    Sponsor's Protocol Code Number:MEDOPP096-MO39229
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2018-03-26
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2016-002676-27
    A.3Full title of the trial
    Chemotherapy-free trastuzumab and pertuzumab in HER2-positive breast cancer: FDG-PET response-adapted strategy. The PHERGain study
    Trastuzumab e pertuzumab sem associação de quimioterapia no cancro da mama HER2 positivo: estratégia de resposta adaptada FDG-PET. O estudo PHERGain
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chemotherapy-free trastuzumab and pertuzumab in HER2-positive breast cancer after FDG-PET response-adapted strategy. The PHERGain study
    Trastuzumab e pertuzumab sem associação de quimioterapia no cancro da mama HER2 positivo após estratégia de resposta adaptada FDG-PET. O estudo PHERGain
    A.3.2Name or abbreviated title of the trial where available
    PHERGain
    PHERGain
    A.4.1Sponsor's protocol code numberMEDOPP096-MO39229
    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 SponsorMedica Scientia Innovation Research (MedSIR)
    B.1.3.4CountrySpain
    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 supportRoche
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedica Scientia Innovation Research (MedSIR)
    B.5.2Functional name of contact pointCrina Popa
    B.5.3 Address:
    B.5.3.1Street AddressGlòries Tower , Av. Diagonal, 211 Floor 27
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08018
    B.5.3.4CountrySpain
    B.5.4Telephone number0034 667 607 730
    B.5.5Fax number0034 932 214 135
    B.5.6E-mailcrina.popa@medsir.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Herceptin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationSwitzerland
    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 nameHerceptin
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous 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 CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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 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 Perjeta
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationSwitzerland
    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 namePerjeta
    D.3.4Pharmaceutical form Concentrate for 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 INNPERTUZUMAB
    D.3.9.1CAS number 380610-27-5
    D.3.9.3Other descriptive namePERTUZUMAB
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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.2.1.1.1Trade name Carboplatino Teva
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Pharma S.L.U.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCarboplatino Teva
    D.3.4Pharmaceutical form Concentrate for 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 INNCarboplatino
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typenot less then
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Docetaxel Accord
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDocetaxel Accord
    D.3.4Pharmaceutical form Concentrate and solvent for 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 INNDOCETAXEL
    D.3.9.3Other descriptive nameDocetaxel
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Letrozol Kern Pharma
    D.2.1.1.2Name of the Marketing Authorisation holderKERN PHARMA S.L
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLetrozol Kern Pharma
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLETROZOLE
    D.3.9.1CAS number 112809-51-5
    D.3.9.3Other descriptive nameLetrozol
    D.3.9.4EV Substance CodeAS5
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    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 Tamoxifeno ratiopharm
    D.2.1.1.2Name of the Marketing Authorisation holderratiopharm España, S.A
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTamoxifeno ratiopharm
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTamoxifeno
    D.3.9.3Other descriptive nameTAMOXIFEN CITRATE
    D.3.9.4EV Substance CodeAS6
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    HER2-positive breast cancer
    Cancro da mama HER2 positivo
    E.1.1.1Medical condition in easily understood language
    Breast cancer
    Cancro da mama
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10065430
    E.1.2Term HER2 positive 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 assess the early metabolic effects of neoadjuvant treatment with trastuzumab and pertuzumab (± endocrine therapy) on the primary tumor and axillary lymph nodes and their predictive value for pathologic complete response (pCR) in the breast and axilla.
    • To assess 3-year invasive disease-free survival (iDFS) in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab (± endocrine therapy) using a FDG-PET response-adapted strategy.
    • Avaliar os efeitos metabólicos iniciais do tratamento neoadjuvante com trastuzumab e pertuzumab (± terapêutica endócrina) no tumor primário e nos nódulos linfáticos axilares e o seu valor preditivo para a resposta patológica completa (pCR) na mama e axila.
    • Avaliar a sobrevivência livre de doença invasiva a 3 anos (iDFS), em doentes com cancro da mama HER2 positivo tratados com terapêutica neoadjuvante com trastuzumab e pertuzumab (± terapêutica endócrina), utilizando uma estratégia de resposta adaptada FDG-PET.
    E.2.2Secondary objectives of the trial
    To assess efficacy by other pCR definitions
    To compare the rate of pCR between the treatment groups by hormone receptor (HR) status and tumor stage
    To compare the rate of conversion to breast conserving surgery
    To compare the overall response rate (ORR) by 18F-FDG PET/CT
    To analyze optimal 18F-FDG PET/CT cut-off for pCR
    To analyze other 18F-FDG PET quantification parameters beside SUVmax for pCR
    To compare the ORR by MRI
    To evaluate changes in health-related quality of life assessments from baseline using the EORTC QLQ-C30 and QLQ-BR23 questionnaires
    To assess 3, 5 and 7-year iDFS
    To assess 3, 5 and 7-year distant disease-free survival (DDFS)
    To assess 3, 5 and 7-year disease-free survival (DFS)
    To assess 3, 5 and 7-year adapted IDFS, DDFS and DFS - cohort C
    To assess 3, 5 and 7-year event-free survival
    To assess 3, 5 and 7-year overall survival (OS)
    To assess progression-free survival (PFS)
    To assess safety outcomes
    Avaliar a eficácia através de outras definições de pCR
    Comparar a taxa de pCR entre os grupos de tratamento relativamente ao status de expressão do recetor hormonal (RH) e ao estádio do tumor
    Comparar a taxa de conversão para cirurgia de conservação da mama
    Comparar a taxa de resposta global (ORR) através de 18F-FDG PET/CT
    Analisar o ponto de corte ótimo de 18F-FDG PET/CT para a pCR
    Analisar outros parâmetros de quantificação por 18F-FDG PET além da SUVmax para a pCR
    Comparar a ORR entre os grupos de tratamento por IRM
    Avaliar alterações nas avaliações da qualidade de vida relacionada com saúde, desde o início do estudo
    Avaliar a iDFS a 3, 5 e 7 anos
    Avaliar a DDFS a 3, 5 e 7 anos
    Avaliar a DFS a 3, 5 e 7 anos
    Avaliar a iDFS, DDFS e DFS adaptadas aos 3, 5 e 7 anos - coorte C
    Avaliar a sobrevivência livre de eventos (EFS) aos 3, 5 e 7 anos
    Avaliar a sobrevivência global (OS) a 3, 5 e 7 anos
    Avaliar a sobrevivência livre de progressão (PFS)
    Avaliar resultados de segurança
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Objective: To identify a new gene expression-based signature predictive of trastuzumab and pertuzumab ± endocrine therapy benefit.
    Objetivo: Identificar uma nova assinatura de expressão genética preditiva do benefício terapêutico do trastuzumab e pertuzumab ± terapêutica endócrina.
    E.3Principal inclusion criteria
    1) Written informed consent prior to beginning specific protocol procedures.
    2) Female or male patients ≥ 18 years of age.
    3) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
    4) Histologically proven invasive breast cancer.
    5) Operable breast cancer (cT1-3 and/or cN0-2 tumors).
    6) Tumor size larger than or equal to 1.5 centimeter (cm) in diameter by magnetic resonance imaging (MRI) or ultrasound with a significant 18F-FDG uptake defined as maximum standardized uptake value (SUVmax) ≥1.5 x SUVmean liver + 2 SD.
    Multicentric/multifocal tumors will be allowed only if:
    1. Histological confirmation of at least two lesions.
    2. All tumors must be HER2-positive.
    3. Largest lesion must be larger than or equal to 1.5 cm in diameter by MRI or ultrasound.
    7) Centrally confirmed HER2-positive disease according to the 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria.
    8) Patient must have known estrogen receptor (ER) and progesterone receptor (PR) status locally determined prior to study entry.

    Patient has adequate bone marrow, liver, and renal function:

    9) Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
    10) Hepatic: total bilirubin ≤ institutional upper limit of normal (ULN) (except for Gilbert’s syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 times ULN.
    11) Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
    12) Patient must be accessible for treatment and follow-up.
    1) Consentimento informado por escrito, anterior ao início de procedimentos específicos do protocolo.
    2) Doentes do sexo feminino ou masculino com idade ≥ 18 anos.
    3) Índice de desempenho de 0-1 na escalaEastern Cooperative Oncology Group (ECOG).
    4) Cancro da mama invasivo histologicamente documentado.
    5) Cancro da mama operável (tumores cT1-3 e/ou cN0-2).
    6) Dimensão do tumor superior ou igual a 1,5 centímetros (cm) em diâmetro, através de imagem de ressonância magnética (IRM) ou ultrassons com uma captação significativa de 18F-FDG definida como o valor máximo de captação normalizado (SUVmax) ≥1,5 x SUVmed fígado + 2 SD.
    Serão permitidos tumores multicêntricos/multifocais, apenas se:
    1. Confirmação histológica de pelo menos duas lesões.
    2. Todos os tumores têm de ser HER2 positivos.
    3. As lesões de maiores dimensões têm de ser superiores ou iguais a 1,5 cm em diâmetro, determinadas através de IRM ou ultrassons.
    7) Doença HER2 positiva confirmada centralmente, de acordo com os critérios da American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) de 2013.
    8) Os doentes devem ter o seu status de expressão dos recetores de estrogénio (RE) e dos recetores de progesterona (RP) conhecido, determinado localmente antes da entrada no estudo.

    Os doentes apresentam função adequada a nível da medula óssea, hepático e renal:

    9) A nível hematológico: Contagem de células brancas (CCB) > 3,0 x 109/L, contagem absoluta de neutrófilos (CAN) ≥ 1,5 x 109/L, contagem de plaquetas ≥ 100,0 x109/L e hemoglobina ≥ 10,0 g/dL (≥ 6,2 mmol/L).
    10) A nível hepático: bilirrubina total ≤ limite superior normal (LSN) institucional (exceto para a síndrome de Gilbert); fosfatase alcalina (FA) ≤ 2,5 vezes LSN; aspartato aminotransferase (AST) e alanina aminotransferase (ALT) ≤ 1,5 vezes LSN.
    11) A nível renal: creatinina sérica ≤ 1,5 x LSN ou depuração da creatinina ≥ 50 ml/min/1,73 m2 para doentes com níveis de creatinina superiores ao normal institucional.
    12) O doente deve estar acessível para tratamento e seguimento.
    E.4Principal exclusion criteria
    1) Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer.
    2) cT4 and/or cN3 tumors.
    3) Bilateral breast cancer.
    4) Evidence of metastatic disease by routine clinical assessment chest x-ray, liver ultrasound, and bone scan; or computed tomography (CT) scan of thorax and abdomen and bone scan, except patients with subclinic M1 at baseline only according to 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) that will be allowed to be included into Cohort C.
    5) Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances.
    6) History of other malignancy within the last five years prior to first dose of study drug administration, except for curatively treated basal and squamous cell carcinoma of the skin and/or in situ cervical carcinoma.
    7) Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO).
    8) Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.
    9) Clinically significant cardiovascular disease [stroke, unstable angina pectoris, or documented myocardial infarction within six months prior to study entry; history of documented congestive heart failure (CHF) (New York Heart Association II-III-IV); symptomatic pericarditis; documented cardiomyopathy; ventricular arrytmhias with the exception of benign premature ventricular contractions; conduction abnormality requiring a pacemaker; other arrhythmias not controlled with medication].
    10) Active uncontrolled infection at the time of enrollment.
    11) Current known infection with HIV, hepatitis B virus, or hepatitis C virus.
    12) Patients with pulmonary disease requiring continuous oxygen therapy.
    13) Previous history of bleeding diathesis.
    14) Patient is currently receiving anti-coagulant therapy, chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).
    15) Major surgical procedure or significant traumatic injury within 14 days prior to randomization or anticipation of need for major surgery within the course of the study treatment.
    16) Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator´s judgment, contraindicate her participation in the clinical study.
    17) Concurrent participation in other clinical trial, except other translational studies.
    18) History of receiving any investigational treatment within 28 days prior to randomization.
    19) Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol.
    1) Tratamento anterior com quimioterapia, terapêutica anti-HER2, radioterapia ou terapêutica endócrina para cancro da mama invasivo.
    2) Tumores cT4 e/ou cN3.
    3) Cancro da mama bilateral.
    4) Evidência de doença metastática através de avaliação clínica de rotina por raio x ao tórax, ultrassons hepático e exame ósseo; ou tomografia computadorizada (CT) do tórax e abdómen e exame ósseo, exceto doentes com M1 subclínicas determinadas no início do estudo apenas através de tomografia por emissão de positrões com 18F-fluordeoxiglicose (18F-FDG)/tomografia computadorizada (PET/CT) , que serão autorizados a ser incluídos na Coorte C.
    5) Reação de hipersensibilidade conhecida a qualquer composto investigacional ou terapêutico ou às suas substâncias incorporadas.
    6) Antecedentes de outra doença maligna nos últimos cinco anos anteriores à administração da primeira dose do fármaco em estudo, exceto para carcinoma das células escamosas e das células basais da pele e/ou carcinoma cervical in situ, tratados de forma curativa.
    7) Fração de ejeção ventricular esquerda (FEVE) inferior a 55%, determinada através de cintilografia de aquisição com regulação múltipla (MUGA) ou ecocardiografia (ECG).
    8) Hipertensão não controlada (sistólica > 150 mm Hg e/ou diastólica > 100 mm Hg), apesar de tratamento anti-hipertensivo adequado.
    9) Doença cardiovascular clinicamente significativa [acidente vascular cerebral, angina de peito instável ou enfarte do miocárdio documentado nos últimos seis meses anteriores à entrada no estudo; história documentada de insuficiência cardíaca congestiva (ICC) (New York Heart Association II-III-IV); pericardite sintomática; cardiomiopatia documentada; arritmias ventriculares com exceção de pré-excitação ventricular benigna; anomalias na condução necessitando de pacemaker; outras arritmias não controladas com medicação].
    10) Infeção ativa não controlada no momento do recrutamento.
    11) Infeção atual conhecida com VIH, vírus da hepatite B ou vírus da hepatite C.
    12) Doentes com doença pulmonar necessitando de oxigenoterapia contínua.
    13) História prévia de diátese hemorrágica.
    14) Doentes atualmente a receber terapêutica anticoagulante, tratamento crónico com corticosteroides ou outro agente imunossupressor (pré-medicação habitual para quimioterapia ou aplicações locais são permitidas).
    15) Procedimento cirúrgico major ou lesão traumática significativa nos 14 dias anteriores à aleatorização ou antecipação da necessidade de uma cirurgia major no decurso do tratamento do estudo.
    16) Doentes com outras condições médicas concomitantes graves e/ou não controladas, que no entendimento do investigador constituam contraindicação para a sua participação no estudo clínico.
    17) Participação simultânea noutro ensaio clínico, exceto outros estudos transversais.
    18) Antecedentes de outro tratamento investigacional nos 28 dias anteriores à aleatorização.
    19) Mulheres grávidas ou a amamentar ou doentes que não estejam dispostos a utilizar métodos contracetivos de elevada eficácia, como definido no protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    • The first co-primary endpoint is to evaluate the rate of pCR as defined by the absence of invasive disease in the breast and axilla (ypT0/isN0) at the time of surgery achieved with the combination of trastuzumab and pertuzumab (± endocrine therapy) as exclusive neoadjuvant treatment in PET responders patients (cohort B/PET responders) [PET/CT positive predictive value (PPV) for a pCR among patients who are PET responders].
    • The second co-primary endpoint is to evaluate 3-year iDFS rate defined as time from the first date of no disease (i.e., date of surgery) to invasive recurrence, new invasive disease, or death by any cause. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria. The primary analysis will be to estimate 3-year iDFS rate in cohort B.
    • O primeiro parâmetro de avaliação final coprimário é a avaliação da taxa de pCR, tal como definida pela ausência de doença invasiva na mama e axila (ypT0/isN0), no momento da cirurgia, obtida através da combinação de trastuzumab e pertuzumab (± terapêutica endócrina) como tratamento neoadjuvante exclusivo em doentes respondedores PET (coorte B/respondedores PET) [valor preditivo positivo PET/CT (VPP) para a pCR entre doentes que são respondedores PET].
    • O segundo parâmetro de avaliação final coprimário é a avaliação da taxa iDFS a 3 anos, definida como o intervalo de tempo desde a primeira data sem doença (i.e. a data da cirurgia) até uma recorrência invasiva, nova doença invasiva ou morte por qualquer causa. A recorrência será definida de acordo com os critérios dos parâmetros de eficácia normalizados (STEEP). A análise primária será efetuada para estimar a taxa de iDFS a 3 anos na coorte B.
    E.5.1.1Timepoint(s) of evaluation of this end point
    -pCR at the time of surgery
    -iDFS rate: 3 years from surgery
    -Taxa de pCR na altura da cirurgia
    -iDFS: 3 anos após cirurgia
    E.5.2Secondary end point(s)
    • pCR rates in the breast and axilla (ypT0/isN0) (cohort A; cohort B; cohort B/PET non-responders).
    • pCR rates in the breast (ypT0/is) (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
    • RCB score (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
    • pCR rates in the breast and axilla (ypT0/isN0) according to HR status and tumor stage (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
    • Rate of breast conserving surgery (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
    • 18F-FDG PET/CT response rate (according to the adapted EORTC criteria) (cohort A; cohort B).
    • Optimal 18F-FDG PET/CT cut-off for pCR (cohort A; cohort B).
    • Other 18F-FDG PET quantification parameters beside SUVmax for pCR (cohort A; cohort B).
    • MRI response rate (according to the RECIST criteria version 1.1) (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
    • Health-related quality of life (EORTC QLQ-C30 and QLQ-BR23 questionnaires) (cohort A; cohort B; cohort C).
    • 3, 5 and 7-year iDFS (cohort A, cohort B, cohorts A/B by PET responder status, HR status, and HER2 status).
    • 3, 5 and 7-year DDFS (cohort A; cohort B, cohorts A/B by PET responder status, HR status, and HER2 status).
    • 3, 5 and 7-year DFS (cohort A; cohort B, cohorts A/B by PET responder status, HR status, and HER2 status).
    • 3, 5, and 7-year adapted iDFS, DDFS, and DFS (patients with subclinical M1 at baseline by 18F-FDG PET/CT – cohort C).
    • 3, 5, and 7-year EFS (cohort A; cohort B)
    • 3, 5 and 7-year OS (cohort A; cohort B; cohort C).
    • PFS (patients with subclinical M1 at baseline by 18F-FDG PET/CT – cohort C).
    • Adverse events, grade 3-4 adverse events, related adverse events, serious adverse events, related serious adverse events, and adverse events leading to discontinuation (cohort A; cohort B; cohort C; cohorts A/B by PET responder status, HR status, and HER2 status).
    • Taxas de pCR na mama e axila (ypT0/isN0) (coorte A; coorte B; coorte B/não respondedores PET).
    • Taxas de pCR na mama (ypT0/is) (coorte A; coorte B; coorte B/respondedores PET; coorte B/não respondedores PET).
    • Pontuação RCB (coorte A; coorte B; coorte B/respondedores PET; coorte B/não respondedores PET).
    • Taxas de pCR na mama e axila (ypT0/isN0) de acordo com o status de expressão do RH e estádio do tumor (coorte A; coorte B; coorte B/respondedores PET; coorte B/não respondedores PET).
    • Taxa de conservação da mama após cirurgia (coorte A; coorte B; coorte B/respondedores PET; coorte B/não-respondedores PET).
    • Taxa de resposta 18F-FDG PET/CT (de acordo com os critérios adaptados EORTC) (coorte A; coorte B).
    • Ponto de corte ótimo de 18F-FDG PET/CT para pCR (coorte A; coorte B).
    • Outros parâmetros de quantificação por 18F-FDG PET além de SUVmax para a pCR (coorte A; coorte B).
    • Taxa de resposta IRM (de acordo com os critérios RECIST versão 1.1) (coorte A; coorte B; coorte B/respondedores PET; coorte B/não respondedores PET).
    • Qualidade de vida relacionada com a saúde (questionários EORTC QLQ-C30 e QLQ-BR23) (coorte A; coorte B; coorte C).
    • iDFS a 3, 5 e 7 anos (coorte A; coorte B; coortes A/B através do status de resposta à PET, status RH e status HER2).
    • DDFS a 3, 5 e 7 anos (coorte A; coorte B; coortes A/B através do status de resposta à PET, status RH e status HER2).
    • DFS a 3, 5 e anos (coorte A; coorte B; coortes A/B através do status de resposta à PET, status RH e status HER2).
    • iDFS, DDFS e DFS adaptadas aos 3, 5 e 7 anos (doentes com M1 subclínicas no início do estudo através de 18F-FDG PET/CT – coorte C).
    • EFS aos 3, 5 e 7 anos (coorte A; coorte B).
    • OS aos 3, 5 e 7 anos (coorte A; coorte b; coorte C; coortes A/B através do status de resposta à PET, status RH e status HER2).
    • PFS (doentes com M1 subclínicas no início do estudo através de 18F-FDG PET/CT – coorte C)
    • Eventos adversos, eventos adversos de grau 3-4, eventos adversos relacionados, eventos adversos graves, eventos adversos graves relacionados e eventos adversos que levam à descontinuação (coorte A; coorte B; coorte C; coortes A/B através do status de resposta a PET, status de RH e status HER2).
    E.5.2.1Timepoint(s) of evaluation of this end point
    3, 5 and 7 years from surgery
    3, 5 e 7 anos após cirurgia
    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 No
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    Disease-free survival (iDFS)
    Sobrevivência livre de doença invasiva
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Os 3 braços A, B e C são comparados em paralelo
    The three arms A, B and C are compared in parallel
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee 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
    The end of study will be seven years from surgery (for cohorts A and B and for cohort C only if surgery is performed), up to seven years from randomization of the last patient (for cohort C if surgery is not performed), or the trial is terminated by the sponsor, whichever occurs first. This data point will be considered LPLV (Last Patient Last Visit).
    O fim do estudo irá ocorrer 7 anos após cirurgia (para os braços A e B e para o braço C apenas se a cirurgia for realizada); até 7 anos após a aleatorização do último doente (para o braço C se cirurgia for realizada); ou o estudo é encerrado pelo promotor, conforme o que ocorrer primeiro.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months7
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male 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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 400
    F.4.2.2In the whole clinical trial 400
    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)
    Standard of care
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-17
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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