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    Summary
    EudraCT Number:2018-001881-40
    Sponsor's Protocol Code Number:BO40747
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2018-10-25
    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 number2018-001881-40
    A.3Full title of the trial
    A phase III, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of Atezolizumab or placebo in combination with neoadjuvant doxorubicin + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab in early HER2-positive breast cancer
    ENSAYO CLÍNICO FASE III DOBLE CIEGO, RANDOMIZADO , CONTROLADO CON PLACEBO, PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DE ATEZOLIZUMAB O PLACEBO EN COMBINACIÓN CON DOXORUBICINA+ CICLOFOSFAMIDA COMO TRATAMIENTO NEOADYUVANTE, SEGUIDO DE PACLITAXEL +TRASTUZUMAB+PERTUZUMAB, EN PACIENTES CON CÁNCER DE MAMA PRECOZ HER2-POSITIVO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Efficacy and Safety of Atezolizumab or Placebo in Combination with Neoadjuvant Doxorubicin + Cyclophosphamide Followed by Paclitaxel + Trastuzumab +Pertuzumab in Early HER2-Positive Breast Cancer
    ESTUDIO PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DE ATEZOLIZUMAB O PLACEBO EN COMBINACIÓN CON DOXORUBICINA+ CICLOFOSFAMIDA COMO TRATAMIENTO NEOADYUVANTE, SEGUIDO DE PACLITAXEL +TRASTUZUMAB+PERTUZUMAB, EN PACIENTES CON CÁNCER DE MAMA PRECOZ HER2-POSITIVO
    A.3.2Name or abbreviated title of the trial where available
    IMpassion050
    A.4.1Sponsor's protocol code numberBO40747
    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 SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.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 Yes
    D.2.1.1.1Trade name Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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.3.1Product nameAtezolizumab
    D.3.2Product code RO5541267/F03
    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 INNATEZOLIZUMAB
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameTecentriq / MPDL3280A
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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: 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 GmbH
    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.3.1Product namePertuzumab (rhuMAb 2C4)
    D.3.2Product code RO4368451/F01
    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.3.9.2Current sponsor codeRO4368451
    D.3.9.3Other descriptive namerhuMAb 2C4
    D.3.9.4EV Substance CodeSUB16455MIG
    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 Herceptin®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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.3.1Product nameTrastuzumab
    D.3.2Product code RO0452317/V03
    D.3.4Pharmaceutical form Powder for 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 INNTRASTUZUMAB
    D.3.9.1CAS number 180288-69-1
    D.3.9.2Current sponsor codeRO452317
    D.3.9.3Other descriptive nameHerceptin
    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 Yes
    D.3.11.13.1Other medicinal product typeHumanized monoclonal antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Early Human epidermal growth factor receptor 2 (HER2)-positive breast cancer
    Cáncer de mama positivo para receptor HER2
    E.1.1.1Medical condition in easily understood language
    HER2-positive breast cancer refers to breast cancer that tests positive for HER2 protein, which promotes the growth of cancer cells
    Cáncer de mama positivo para receptor HER2 se refiere a un cáncer que es positivo para la proteína HER2 que estimula el crecimiento de las células cancerígenas
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate the efficacy of atezolizumab + dose-dense anthracycline (doxorubicin + cyclophosphamide) followed by paclitaxel + trastuzumab + pertuzumab [ddAC-PacHP] compared with placebo + ddAC-PacHP in the early breast cancer (EBC) on basis of Pathological complete response (pCR)
    En este estudio (que se conoce también como IMpassion050) se evaluará la eficacia y la seguridad de atezolizumab comparado con placebo cuando se administra en combinación con quimioterapia neoadyuvante con dosis densas de antraciclinas (doxorubicina + ciclofosfamida)
    seguido de paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) en pacientes con cáncer de mama precoz HER2-positivo con alto riesgo de recurrencia (T2-4, N1-3, M0).
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of atezolizumab + ddAC-PacHP compared with placebo + ddAC-PacHP in the EBC on basis of pCR (ypT0/is ypN0) based upon hormone receptor status, pCR (ypT0/is ypN0), PD-L1 status, Event-free survival (EFS), Disease-free survival (DFS), Overall survival (OS)
    • To evaluate patient-reported outcomes (PROs) of function and health-related quality of life (HRQoL) associated with atezolizumab + ddAC-PacHP compared with ddAC-PacHP alone, as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)
    • To evaluate the safety of atezolizumab + ddAC-PacHP compared with placebo + ddAC-PacHP in the EBC
    • To characterize the pharmacokinetic profile of atezolizumab, pertuzumab, and trastuzumab when given in combination
    • To evaluate the immune response to atezolizumab, trastuzumab, and pertuzumab
    El objetivo principal de eficacia de este estudio es evaluar la eficacia de atezolizumab + ddAC-PacHP comparado con placebo + ddAC-PacHP en el entorno del cáncer de mama precoz (CMP), basándose en la siguiente variable respuesta completa patológica (RCp) inidice PD-L1, supervivencia libre de eventos, supervivencia libre de enfermedad, supervivencia global
    Evaluar los resultados reportados por los pacientes (PRO) de función y calidad de vida relacionada con la salud (CVRS) asociados con atezolizumab + ddAC-PacHP comparado con ddAC-PacHP solo, mediante el European Organisation for Research and Treatment of
    Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)
    Evaluar la seguridad de atezolizumab + ddAC-PacHP comparada con placebo + ddAC-PacHP
    Caracterizae el perfil farmacocinetico de atezolizumab, pertuzumab, y trastuzumab en combinación
    Evaluar la respuesta inmune a atezolizumab, trastuzumab, and pertuzumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age >= 18 years
    • Ability to comply with the study protocol, in the investigator's judgment
    • Confirmed diagnosis of HER2-positive breast cancer, and hormonal and programmed death-ligand 1 (PD-L1) status, as documented through central testing of a representative tumor tissue specimen, is required
    • Primary breast tumor size of > 2 cm by radiographic measurement
    • Stage at presentation: T2-T4, N1-N3, M0 as determined by American Joint Committee on Cancer staging system, 8th edition
    • Pathologic confirmation of nodal involvement with malignancy must be determined by fine-needle aspiration or core-needle biopsy. Surgical excision of lymph nodes is not permitted
    • Patients with multifocal tumors or multicentric tumors are eligible provided all discrete lesions are sampled and centrally confirmed as HER2-positive
    • In patients with multifocal or multicentric breast cancer, the largest lesion should be measured to determine T stage
    • Patients with synchronous bilateral invasive disease are eligible so long as both lesions are HER2-positive
    • In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint
    • Patient agreement to undergo appropriate surgical management, including axillary lymph node surgery and partial or total mastectomy, after completion of neoadjuvant treatment
    • Eastern Cooperative Oncology Group Performance Status of 0 or 1
    • Baseline left ventricular ejection fraction >= 55% measured by echocardiogram or multiple-gated acquisition scans
    • Adequate hematologic and end-organ function
    • Negative HIV test at screening
    • Negative hepatitis B surface antigen (HBsAg) and negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
    • Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
    • For women of childbearing potential: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating eggs, Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final dose of atezolizumab/placebo, 6 months after the final dose of doxorubicin, 12 months after the final dose of cyclophosphamide, 6 months after the final dose of paclitaxel, and 7 months after the final dose of trastuzumab and/or pertuzumab, whichever occurs last
    • For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the final dose of doxorubicin and/or cyclophosphamide, 6 months after the final dose of paclitaxel, and 7 months after the final dose of trastuzumab and/or pertuzumab, whichever occurs last
    · Firmar el formulario de consentimiento informado
    · Tener ³ 18 años en el momento de la firma del formulario de consentimiento informado
    · Capacidad para cumplir los requisitos del protocolo del estudio, de acuerdo con el criterio del investigador
    · Se requiere el diagnóstico confirmado de cáncer de mama HER2-positivo y del estado de receptores hormonales y de PD-L1, documentado mediante el análisis en el laboratorio central de una muestra representativa de tejido tumoral.
    El tumor de mama primario debe ser >2 cm, medido en la evaluación radiológica
    · Estadio en el momento de la presentación clínica: T2-T4, N1-N3, M0 determinado basándose en el sistema de estadificación de la AJCC, 8ª edición (específicamente, de acuerdo con las normas del Anatomic Stage Group)
    · La confirmación histopatológica de la afectación ganglionar por el tumor se debe determinar mediante aspirado con aguja fina o biopsia con aguja gruesa. No está permitida la escisión quirúrgica de los ganglios linfáticos (biopsia del ganglio centinela y de ganglios linfáticos axilares).
    · Los pacientes con tumores multifocales (más de un tumor confinado al mismo cuadrante que el tumor primario) o multicéntricos (varios tumores en más de un cuadrante) son elegibles siempre que se tomen muestras de todas las diferentes lesiones y se confirme que son HER2-positivo en el laboratorio central.
    · En los pacientes con cáncer de mama multifocal o multicéntrico, se debe medir la lesión de mayor tamaño para determinar el estadio T.
    · Los pacientes con cáncer de mama bilateral sincrónico invasivo son elegibles siempre que ambas lesiones sean HER2-positivo.
    · En el caso del cáncer de mama bilateral, el investigador debe decir prospectivamente qué lado se utilizará para la evaluación de la variable principal.
    · Aceptación por parte del paciente a someterse a una intervención quirúrgica adecuada, incluyendo linfadenectomía axilar y mastectomía parcial o total, después de completar el tratamiento neoadyuvante
    · Estado funcional del Eastern Cooperative Oncology Group 0 o 1
    FEVI basal ³ 55%, valorada en ecocardiograma (ECO) o angiografía radioisotópica (MUGA)
    · Función hematológica y de órganos diana adecuada, definida por los resultados de las pruebas de laboratorio siguientes obtenidos en los 14 días previos al inicio del tratamiento del estudio
    Prueba de VIH negativa en el período de selección
    · Prueba negativa para el antígeno de superficie de hepatitis B (HBsAg) en el período de selección
    · Prueba negativa total para anticuerpos contra el núcleo del virus de hepatitis B (HBcAb) en el período de selección o prueba positiva total para HBcAb, seguida de una prueba de ADN negativa para el virus de la hepatitis B (VHB) en dicho período
    Prueba negativa para anticuerpos contra el virus de la hepatitis C (VHC) en el período de selección o prueba positiva para anticuerpos contra VHC, seguida de una prueba de ARN negativa para VHC en dicho período
    Las mujeres potencialmente fértiles deben comprometerse a practicar la abstinencia sexual (es decir, abstenerse de mantener relaciones heterosexuales) o a usar métodos anticonceptivos, así como a no donar óvulos
    Los varones deben comprometerse a practicar la abstinencia sexual (es decir, abstenerse de mantener relaciones heterosexuales) o a usar métodos anticonceptivos, así como a no donar semen
    E.4Principal exclusion criteria
    • Prior history of invasive breast cancer
    • Stage IV (metastatic) breast cancer
    • Prior systemic therapy for treatment of breast cancer
    • Previous therapy with anthracyclines or taxanes for any malignancy
    • Ulcerating breast cancer
    • Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes
    • Sentinel lymph node procedure or axillary lymph node dissection prior to initiation of neoadjuvant therapy
    • History of other malignancy within 5 years prior to screening, with the exception of those who patients have a negligible risk of metastasis or death, such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
    • Cardiopulmonary dysfunction
    • Dyspnea at rest
    • Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis
    • History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
    • Active tuberculosis
    • Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the study
    • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
    • Treatment with therapeutic antibiotics within 2 weeks (IV antibiotics) or 5 days (oral antibiotics) prior to initiation of study treatment
    • Prior allogeneic stem cell or solid organ transplantation
    • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug and may affect the interpretation of the results, or may render the patient at high risk from treatment complications
    • Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab/placebo treatment or within 5 months after the final dose of atezolizumab/placebo
    • Treatment with investigational therapy within 28 days prior to initiation of study treatment
    • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
    • Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
    • Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
    • History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
    • Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
    • Known allergy or hypersensitivity to the components of the paclitaxel, cyclophosphamide, or doxorubicin formulations
    • Known allergy or hypersensitivity to trastuzumab or pertuzumab formulations
    • Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab/placebo, 6 months after the final dose of doxorubicin, 12 months after the final dose of cyclophosphamide, 6 months after the final dose of paclitaxel, or 7 months after the final dose of trastuzumab and/or pertuzumab, whichever occurs last. Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment
    Antecedentes de cáncer de mama invasivo
    ·Cáncer de mama en estadio IV (metastásico)
    Tratamiento sistémico previo para cáncer de mama
    ·Tratamiento previo con antraciclinas o taxanos para cualquier neoplasia maligna
    ·Cáncer de mama ulcerado
    ·Biopsia por incisión y/o escisión del tumor primario y/o ganglios linfáticos axilares
    ·Procedimiento del ganglio centinela o linfadenectomía axilar antes de iniciar el tratamiento neoadyuvante
    ·Antecedentes de otras neoplasias malignas en los 5 años previos a la selección, exceptuando aquellas que tengan un riesgo insignificante de metástasis o muerte (p. ej. tasa de SG a 5 años >90%),tales como carcinoma in situ de cérvix, carcinoma de piel distinto de melanoma, cáncer de próstata localizado, carcinoma ductal in situ o cáncer de útero en estadio I tratados adecuadamente
    ·Disfunción cardiopulmonar, definida como cualquiera de las siguientes, antes de la randomización
    Disnea en reposo
    ·Antecedentes o presencia de enfermedades autoinmunes o inmunodeficiencias, incluyendo
    aunque no exclusivamente, miastenia gravis, miositis, hepatitis autoinmune lupus eritematoso sistémico,artritis reumatoide,enfermedad inflamatoria intestinal, síndrome de anticuerpos antifosfolípidos, granulomatosis de Wegener, síndrome de Sjögren, síndrome de Guillain-Barré o esclerosis múltiple (se puede consultar el protocolo para ver una lista más amplia de enfermedades autoinmunes e inmunodeficiencias)
    Antecedentes de fibrosis pulmonar idiopática, neumonía organizada (p. ej. bronquiolitis obliterante), neumonitis inducida por fármacos o neumonitis idiopática o evidencia de neumonitis activa en la tomografía axial computarizada (TAC) de tórax realizada en el período de selección
    Tuberculosis activa
    ·Procedimientos de cirugía mayor,salvo que sean con fines diagnósticos, en las 4 semanas previas al inicio del tratamiento del estudio o que previsiblemente sean necesarios durante el estudio
    ·Infecciones graves en las 4 semanas previas al inicio del tratamiento del estudio incluyendo, aunque no exclusivamente, infecciones complicadas que requieran hospitalización, bacteremia o neumonía grave
    Tratamiento con antibióticos con fines terapéuticos en las 2 semanas previas (para los
    antibióticos IV) o los 5 días previos (para los antibióticos orales) al inicio del tratamiento del estudio
    Trasplante previo alogénico de células madre o de órganos sólidos
    ·Cualquier otra enfermedad,trastorno metabólico,hallazgo de la exploración física o de las pruebas de laboratorio clínico para los cuales está contraindicado el uso de un fármaco en investigación y que puedan afectar a la interpretación de los resultados o implicar para el paciente un riesgo alto de complicaciones relacionadas con el tratamiento
    Administración de vacunas vivas atenuadas en las 4 semanas previas al inicio del tratamiento del estudio o que previsiblemente sean necesarias durante el tratamiento con atezolizumab/placebo o en los 5 meses siguientes a la administración de la última dosis de atezolizumab/placebo
    ·Tratamiento con un agente en investigación en los 28 días previos al inicio del tratamiento del estudio
    ·Tratamiento previo con agonistas de CD137 o inhibidores de puntos de control inmunitario,incluyendo inhibidores del antígeno 4 asociado a linfocitos T citotóxicos y anticuerpos terapéuticos anti-PD-1 y anti-PD-L1
    · Tratamiento con agentes inmunoestimuladores sistémicos (incluyendo,aunque no exclusivamente,interferones e interleuquina-2[IL-2]) en las 4 semanas previas al inicio del tratamiento del estudio o durante el equivalente a 5 semividas del fármaco (lo que sea más prolongado)
    · Tratamiento con agentes inmunosupresores sistémicos (incluyendo,aunque no exclusivamente, corticosteroides, ciclofosfamida, azatioprina, metotrexato, talidomida e inhibidores del factor a de necrosis tumoral [TNF-a]) en las 2 semanas previas al inicio del tratamiento del estudio o que previsiblemente sean necesarios durante el tratamiento del estudio
    Antecedentes de reacciones alérgicas anafilácticas graves a anticuerpos quiméricos o humanizados o a proteínas de fusión
    · Hipersensibilidad conocida a productos elaborados con células de ovario de hámster chino o a cualquiera de los componentes de la formulación de atezolizumab
    · Alergia o hipersensibilidad conocidas a los componentes de las formulaciones de paclitaxel, ciclofosfamida o doxorubicina
    · Alergia o hipersensibilidad conocidas a las formulaciones de trastuzumab o pertuzumab
    · Mujeres embarazadas, en período de lactancia o que tengan intención de quedarse embarazadas durante el tratamiento del estudio o en los 5 meses siguientes a la administración de la última dosis de atezolizumab/placebo, en los 6 meses siguientes a la última dosis de doxorubicina, en los 12 meses siguientes a la última dosis de ciclofosfamida, en los 6 meses siguientes a la última dosis de paclitaxel o en los 7 meses siguientes a la última dosis de trastuzumab y/o pertuzumab, lo que ocurra en último lugar
    E.5 End points
    E.5.1Primary end point(s)
    1. pCR
    Respuesta completa patológica (RCp)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Completion of neoadjuvant treatment and surgery
    Finalización del tratamiento neoadjuvante y cirugía
    E.5.2Secondary end point(s)
    1. pCR (ypT0/is ypN0) based upon hormone receptor status
    2. pCR (ypT0/is ypN0) based upon PD-L1 status (IC 0; IC 1/2/3)
    3. EFS
    4. DFS
    5. OS
    6. Mean and mean changes from baseline score in function (role, physical) and global health status (GHS)/ HRQoL by assessment timepoint, and between treatment arms as assessed by the functional and GHS/HRQoL scales of the EORTC QLQ-C30
    7. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0
    8. Change from baseline in targeted vital signs
    9. Change from baseline in targeted clinical laboratory test results
    10. Maximum serum concentration observed [Cmax] and minimum serum concentration under steady-state conditions within a dosing interval [Cmin]) of atezolizumab concentrations in serum at specified timepoints
    11. Cmin for pertuzumab and trastuzumab in serum at specified timepoints
    12. Incidence of treatment-emergent anti-drug antibodies (ADAs) to atezolizumab, trastuzumab, and pertuzumab
    1. pCR (ypT0/is ypN0) basado en el estado del receptor hormonal
    2. pCR (ypT0/is ypN0) basado en el estado PD-L1 (IC 0; IC 1/2/3)
    3. EFS
    4. DFS
    5. OS
    6. Cambios medios y media de la puntuación basal en función (función, físico) y estado de salud global (SGA) / CVRS según el tiempo de evaluación, y entre los brazos de tratamiento evaluados por las escalas funcional y GHS / CVRS del EORTC QLQ-C30
    7. Incidencia y gravedad de los eventos adversos, con severidad determinada de acuerdo con los Criterios de Terminología Comunes del National Cancer Institute para Eventos Adversos, Versión 5.0
    8. Cambio desde la línea basal en signos vitales específicos
    9. Cambio desde el inicio en los resultados de pruebas de laboratorio clínico
    10. Concentración sérica máxima observada [Cmax] y concentración sérica mínima en condiciones de estado estacionario dentro de un intervalo de dosificación [Cmin]) de las concentraciones de atezolizumab en suero en momentos específicos
    11. Cmin para pertuzumab y trastuzumab en suero en momentos específicos
    12. Incidencia de anticuerpos antifarmacos emergentes por tratamiento (ADA) para atezolizumab, trastuzumab y pertuzumab
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-2. Completion of neoadjuvant treatment and surgery
    3-5. End of study
    6. Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit
    7. Completion of overall treatment period
    8. Baseline (Day 1), Day 1 of Cycle 2-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit
    9. Baseline (Day 1), Day 1 of Cycle 2-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow-up visits
    10-12 Day 1 of Cycle 1, 2, 3, 4, 8, 12, 16, at treatment discontinuation visit
    1-2. Finalización del tratamiento neoadjuvante y cirugía
    3-5. Fin de estudio
    6. Día 1 de los ciclos 1-9, en el día 1 de los demás ciclos hasta el ciclo 22; en la descontinuación del tratamiento o fin prematuro y visita de seguimiento
    7. Fin del periodo de tratamiento
    8. Basal (día 1), día 1 de los ciclos 2-9, día 1 de los demás ciclos hasta el ciclo 22; en la descontinuación del tratamiento o fin prematuro
    9. Basal (día 1), día 1 de los ciclos 2-9, día 1 de los demás ciclos hasta el ciclo 22; en la descontinuación del tratamiento o fin prematuro y visita de seguimiento
    10-12 Día 1 del ciclo 1, 2, 3, 4, 8, 12, 16, en la visita de fin de tratamiento
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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
    To evaluate the immune response
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Brazil
    Canada
    Czech Republic
    Germany
    Italy
    Japan
    Korea, Republic of
    Russian Federation
    Spain
    Taiwan
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS, The end of the study is expected to occur approximately 36 months after the last patient is enrolled.
    El fin de estudio se espera aproximadamente a los 36 meses desde que se incluya el último paciente
    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 months2
    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 months2
    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: 202
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 22
    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 No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 135
    F.4.2.2In the whole clinical trial 224
    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)
    The Sponsor does not have any plans to provide Roche IMPs (atezolizumab, pertuzumab, and trastuzumab) or any other study treatments or interventions to patients who have completed the study. The Sponsor may evaluate whether to continue providing atezolizumab, pertuzumab, and trastuzumab in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, available at:
    http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    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 Decision2019-01-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-18
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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