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    Summary
    EudraCT Number:2018-000977-62
    Sponsor's Protocol Code Number:012418QM
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2018-000977-62
    A.3Full title of the trial
    BARBICAN: A randomised, open-label Phase II study to determine the contribution of ipatasertib to neoadjuvant chemotherapy plus atezolizumab in women with triple-negative breast cancer
    BARBICAN: Estudio de fase II abierto y aleatorizado para determinar la contribución de ipatasertib a la quimioterapia neoadyuvante más atezolizumab en mujeres con cáncer de mama triple negativo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    BARBICAN: investigating AKT inhibitors in combination with immunotherapy and chemotherapy in patients with triple negative breast cancer
    BARBICAN: Investigación de los inhibidores de la AKT en combinación con inmunoterapia y quimioterapia en pacientes con cáncer de mama triple negativo
    A.3.2Name or abbreviated title of the trial where available
    BARBICAN
    BARBICAN
    A.4.1Sponsor's protocol code number012418QM
    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 SponsorQueen Mary University of London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLa Hoffmann - Roche Ltd
    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
    B.5.2Functional name of contact pointClinical Trial Unit
    B.5.3 Address:
    B.5.3.1Street AddressRambla de Catalunya, 2, 2D
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08007
    B.5.3.4CountrySpain
    B.5.4Telephone number34932214135
    B.5.6E-mailleonardo.mina@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 Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 nameTecentriq
    D.3.2Product code Atezolizumab
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNATEZOLIZUMAB
    D.3.9.1CAS number 1380723-44-3
    D.3.9.3Other descriptive nameR05541267
    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 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 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 nameIpatasertib
    D.3.2Product code Ipatasertib
    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 INNIPATASERTIB
    D.3.9.3Other descriptive nameRO5532961
    D.3.9.4EV Substance CodeSUB189203
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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: 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 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 nameIpatasertib
    D.3.2Product code Ipatasertib
    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 INNIPATASERTIB
    D.3.9.3Other descriptive nameRO5532961
    D.3.9.4EV Substance CodeSUB189203
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Triple Negative Breast Cancer
    Cáncer de mama triple negativo
    E.1.1.1Medical condition in easily understood language
    Breast cancer negative for oestrogen receptor, progesterone receptor and HER2
    Cáncer de mama negativo para receptor de estrógeno, receptor de progesterona y HER2
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10057654
    E.1.2Term Breast cancer female
    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
    Clinical: To compare the pathologic complete response (pCR) rates of NACT plus atezolizumab with NACT plus atezolizumab plus Ipatasertib in patients with or without PIK3CA/AKT1/PTEN genetic alterations.

    Biological: To determine whether adding the AKT-inhibitor ipatasertib to atezolizumab and chemotherapy increases the probability of an immune response over adding atezolizumab to chemotherapy in all treated patients
    Clínico: Comparar la tasa de respuesta completa patológica (RCp) de la QTNA más atezolizumab con la obtenida con la QTNA más atezolizumab más ipatasertib en pacientes con o sin alteraciones genéticas de PIK3CA/AKT1/PTEN.

    Biológico: Determinar si la adición del inhibidor de AKT ipatasertib a la quimioterapia más atezolizumab aumenta la probabilidad de una respuesta inmunitaria frente a la adición de atezolizumab a la quimioterapia en todas las pacientes tratadas.
    E.2.2Secondary objectives of the trial
    -Determine the response rates of the breast tumour and axillary nodes based on physical examination and imaging tests after treatment in both arms.
    -Assess clinical response rate after taxanes plus atezolizumab in both groups
    -To assess the effect of adding ipatasertib to atezolizumab on additional immune mediated biomarkers.
    -Determine the effect of ipatasertib on IEFS, DEFS and OS
    -Evaluate PROs of health-related quality of life (HRQoL) associated with the addition of ipatasertib, as measured by the EORTC QLQ-C30
    -Assess the safety of each treatment arm.
    - Determinar la tasa de respuesta del tumor mamario y los ganglios axilares, en función de la exploración física y las pruebas de diagnóstico por la imagen después del tratamiento en ambos grupos.
    - Evaluar la tasa de respuesta clínica después del tratamiento con taxanos más atezolizumab en ambos grupos.
    - Evaluar el efecto de la adición de ipatasertib a atezolizumab en biomarcadores adicionales mediados por el sistema inmunitario.
    - Determinar el efecto de ipatasertib en la SSEI, la SSMD y la SG.
    - Evaluar los RNP de la calidad de vida relacionada con la salud (CdVRS) asociada a la adición de ipatasertib, según su determinación mediante el cuestionario QLQ-C30 de la EORTC.
    - Evaluar la seguridad de cada grupo de tratamiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing and able to provide written informed consent prior to study entry
    2. Female ≥ 18 years of age
    3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
    4. Histologically confirmed TNBC defined as:
    •ER negative with <1% of tumour cells positive on IHC or an IHC score (Allred) of ≤2
    • PR unknown or negative with <1% of tumour cells positive on IHC or Allred score of ≤2
    • HER2 negative with 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH
    5. Node-positive (cT1-4 cN1-2 M0) and/or tumour size ≥2 cm (cT2-T4 cN0-2 M0) with no prior treatment; participants entering the trial after undergoing a SLN biopsy will be eligible if they meet other entry criteria
    6. Adequate haematologic and end-organ function within 28 days prior to the first study treatment defined by the following:
    a. ANC ≥ 1500 cells/μL (1.5 x 109/L) (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
    b. Platelet count ≥ 100,000/μL (100 x 109/L) (without transfusion within 2 weeks prior to Cycle 1, Day 1)
    c. Haemoglobin ≥ 9.0 g/dL (90g/L) (patients may be transfused or receive erythropoietic treatment to meet this criterion).
    d. INR or aPTT ≤ 1.5 x ULN (for patients not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation must be on a stable anticoagulant regimen.
    e. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min
    f. AST or ALT and ALP < 2.5 times the institutional upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled).
    7. Patients of childbearing potential are eligible provided they have a negative serum or urine pregnancy test within 14 days of Day 1 Cycle 1 of study treatment, preferably as close to the first dose as possible. Patients must agree to use adequate contraception, defined as those methods with a failure rate of < 1 % per year, (see section 6.14) beginning 14 days before the first dose of study drug and for 12 months after the last dose of cyclophosphamide (or 5 months after the last dose of atezolizumab, whichever is longer).
    8. Ability to comply with the protocol
    9. Representative formalin-fixed paraffin embedded (FFPE) breast tumour samples (at least 2 core needle biopsies) with an associated pathology report, determined to be available and sufficient for central testing OR tumour accessible for biopsy.
    1.Pacientes dispuestos y capaces de proporcionar el consentimiento informado por escrito antes de la inclusión en el estudio.
    2.Mujeres ≥18 años.
    3.Estado funcional de 0 o 1 según el Eastern Cooperative Oncology Group (ECOG).
    4.CMTN confirmado histológicamente, definido como:
    •ER negativo, con positividad de <1 % de las células tumorales según un estudio IHQ o una puntuación de IHQ (Allred) de ≤2
    •PR desconocido o negativo, con positividad de <1 % de las células tumorales según un estudio IHQ o puntuación de Allred de ≤2
    •HER2 negativo, con intensidad de 0, 1+ o 2+ según IHQ y ningún indicio de amplificación del gen HER2 en un estudio de ISH
    5.Afectación ganglionar (cT1-4 cN1-2 M0) y/o del tamaño del tumor ≥2 cm (cT2-T4 cN0-2 M0) sin tratamiento previo; las participantes que entren en el ensayo después de someterse a una biopsia del ganglio centinela serán elegibles si cumplen otros criterios de elegibilidad.
    6.Función hematológica y de órganos específicos adecuada en los 28 días previos al primer tratamiento del estudio, definida de la siguiente forma:
    a.RAN ≥1500 células/μl (1,5 × 109/l) (sin tratamiento complementario con factores estimulantes de colonias de granulocitos en las 2 semanas anteriores al día 1 del ciclo 1).
    b.Número de plaquetas ≥100 000/μl (100 × 109/l) (sin transfusión en las 2 semanas anteriores al día 1 del ciclo 1).
    c.Hemoglobina ≥9,0 g/dl (90 g/l) (las pacientes pueden recibir una transfusión o tratamiento eritropoyético para cumplir este criterio).
    d.INR o TTPa ≤1,5 x LSN (para las pacientes que no reciben anticoagulación terapéutica). Las pacientes que reciben anticoagulación terapéutica deben estar recibiendo una pauta anticoagulante estable.
    e.Creatinina sérica ≤1,5 × LSN o aclaramiento de creatinina calculado de ≥50 ml/min.
    f.Valores de AST o ALT y FA <2,5 veces el límite superior de la normalidad (LSN), bilirrubina ≤1,5 × LSN (se podrá incluir a las pacientes con enfermedad de Gilbert conocida y con una concentración de bilirrubina sérica ≤3 × el LSN del centro).
    7.Las pacientes con posibilidad de quedar embarazadas son elegibles si tienen un resultado negativo en una prueba de embarazo en suero u orina durante los 14 días del día 1 del ciclo 1 del tratamiento del estudio, preferiblemente lo más cerca posible de la primera dosis. Las pacientes deben aceptar el uso de un método anticonceptivo aceptable, definido como los métodos con una tasa de fallo <1 % al año (véase el apartado 6.14), a partir de 14 días antes de la primera dosis del fármaco del estudio y durante 12 meses después de la última dosis de ciclofosfamida (o 5 meses después de la última dosis de atezolizumab, lo que sea más prolongado).
    8.Capacidad de cumplir con el protocolo.
    9.Muestras representativas de los tumores de mama fijadas en formol e incluidas en parafina (FFIP) (al menos 2 biopsias con aguja gruesa) con un informe anatomopatológico asociado, que estarán disponibles y serán suficientes para realizar un análisis centralizado O tumor accesible para biopsia.
    E.4Principal exclusion criteria
    1.Evidence of metastatic breast cancer.
    2.Received any systemic therapy or radiotherapy for current breast cancer disease before study entry
    3.Prior exposure to any CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1 or anti-PD-L1 antibody.
    4.Concurrent bilateral invasive breast cancer
    5.Inflammatory breast cancer
    6.Active malignancy (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) within the past 36 months prior to study entry
    7.Major surgery within the last 28 days or anticipation of the need for major surgery during study treatment; minor surgeries including insertion of an indwelling catheter, core needle biopsy, or sentinel lymph node biopsy is allowed.
    8.Known intolerance to any of the study drugs or any of their excipients
    9.Pre-existing peripheral neuropathy grade ≥ 2
    10.History of autoimmune disease
    11.History of Type I or Type II diabetes mellitus requiring insulin. Patients who are on a stable dose of oral diabetes medication ≥ 2 weeks prior to initiation of study treatment are eligible for enrolment.
    12.History of idiopathic pulmonary fibrosis or organizing pneumonia
    13.History of HIV infection
    14.Known active hepatitis infection or hepatitis C.
    15.Active tuberculosis
    16.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
    17.Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics are eligible for the study.
    18.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 treatment or within 5 months after the final dose of atezolizumab
    19.Current treatment with anti-viral therapy for HBV
    20.Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
    21.Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids (≥10 mg prednisolone or an equivalent dose of other anti-inflammatory corticosteroids) use for ≥28 days at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose of corticosteroids for at least two weeks before randomisation are allowed.
    22.Significant cardiovascular disease.
    23.Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
    24.Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
    25.Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry.
    26.Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug
    27.Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and peripheral neuropathy
    28.Pregnant or nursing women

    For Atezolizumab + Ipatasertib arm only
    1.Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications.
    2.Clinically significant abnormalities of glucose metabolism
    3.History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
    1.Signos de cáncer de mama metastásico.
    2.Haber recibido cualquier tratamiento sistémico o radioterapia contra el cáncer de mama actual antes de la inclusión en el estudio.
    3.Exposición anterior a cualquier agonista de CD137 o tratamientos de bloqueo de los puntos de control inmunitario, incluidos anticuerpos anti-CTLA-4, anti-PD-1 o anti-PD-L1.
    4.Cáncer de mama infiltrante bilateral concurrente.
    5.Cáncer de mama inflamatorio.
    6.Neoplasia maligna activa (excepto cáncer de piel no melanoma o carcinoma localizado confirmado histológicamente y extirpado en su totalidad) en los últimos 36 meses antes de la inclusión en el estudio.
    7.Cirugía mayor en los últimos 28 días o previsión de que se necesite intervención de cirugía mayor durante el tratamiento del estudio; se permiten intervenciones de cirugía menor, incluida la colocación de un catéter permanente, una biopsia con aguja gruesa o una biopsia del ganglio linfático centinela.
    8.Intolerancia conocida a cualquiera de los medicamentos del estudio o alguno de sus excipientes.
    9.Neuropatía periférica preexistente de grado ≥2.
    10.Antecedentes de enfermedad autoinmunitaria.
    11.Antecedentes de diabetes mellitus de tipo I o de tipo II que requiere insulina. Las pacientes que estén recibiendo una dosis estable de medicación oral contra la diabetes ≥2 semanas antes del inicio del tratamiento del estudio son elegibles para la inclusión.
    12.Antecedentes de fibrosis pulmonar idiopática o neumonía organizada.
    13.Antecedentes de infección por el VIH.
    14.Infección por hepatitis activa conocida o hepatitis C.
    15.Tuberculosis activa.
    16.Infección grave en las 4 semanas anteriores al inicio del tratamiento del estudio, incluyendo, entre otros, hospitalización por complicaciones de la infección, bacteriemia o neumonía grave.
    17.Tratamiento con antibióticos orales o i.v. con intención terapéutica en las 2 semanas previas al inicio del tratamiento del estudio. Las pacientes que estén recibiendo antibióticos profilácticos son elegibles para participar en el estudio.
    18.Tratamiento con una vacuna elaborada con virus vivos atenuado en las 4 semanas anteriores al inicio del tratamiento del estudio o previsión de que será necesario administrar esta vacuna durante el tratamiento con atezolizumab o en un plazo de 5 meses después de la última dosis de atezolizumab.
    19.Tratamiento antivírico actual contra la infección por el VHB.
    20.Tratamiento con inmunoestimulantes sistémicos (incluyendo, entre otros, interferón e interleucina 2 [IL-2]) en las 4 semanas o 5 semividas del fármaco (el período más prolongado de los dos) antes de iniciar el tratamiento del estudio.
    21.Pacientes que reciben inmunosupresores o corticosteroides sistémicos crónicos (≥10 mg de prednisolona o una dosis equivalente de otros corticosteroides antiinflamatorios) durante ≥28 días en el momento de su inclusión en el estudio, excepto en los casos indicados a continuación: Se permiten aplicaciones tópicas (p. ej., erupción cutánea), pulverizaciones inhaladas (p. ej., enfermedades obstructivas de las vías respiratorias), colirios o inyecciones locales (p. ej., intraarticulares). Se permiten pacientes que estén lleven recibiendo dosis bajas estables de corticosteroides durante al menos dos semanas antes de la aleatorización.
    22.Enfermedad cardiovascular significativa.
    23.Toda enfermedad, disfunción metabólica, hallazgo en una exploración física o hallazgo analítico clínico que, en opinión del investigador, suscite sospechas razonables de una enfermedad o proceso que contraindique el uso de un medicamento en investigación, que pueda afectar a la interpretación de los resultados, que suponga un riesgo elevado de complicaciones derivadas del tratamiento para el paciente o que interfiera en la obtención del consentimiento informado.
    24.Trastornos psicológicos, familiares, sociológicos o geográficos que no permitan el cumplimiento del protocolo del estudio
    25.Tratamiento concomitante con otros fármacos experimentales. Participación en otro ensayo clínico con cualquier medicamento en investigación en los 30 días anteriores a la entrada en el estudio.
    26.Tratamiento con inhibidores potentes de la CYP3A o inductores potentes de la CYP3A en las 2 semanas o 5 semividas de eliminación del fármaco, lo que sea más prolongado, antes de iniciar el fármaco del estudio.
    27.Toxicidades persistentes (grado ≥2 según los CTCAE) causadas por el tratamiento previo contra el cáncer, excluyendo alopecia y neuropatía periférica.
    28.Mujeres embarazadas o en período de lactancia.

    Solo para el brazo Atezolizumab + Ipatasertib:
    1.Incapacidad de tragar medicamentos o problemas de malabsorción que pudieran alterar la absorción de la medicación administrada por vía oral.
    2.Anomalías clínicamente significativas del metabolismo de la glucosa.
    3.Antecedentes o presencia activa de enfermedad inflamatoria intestinal (p. ej., enfermedad de Crohn y colitis ulcerosa) o inflamación intestinal activa (p. ej., diverticulitis).
    E.5 End points
    E.5.1Primary end point(s)
    Clinical:
    • pCR is defined as no microscopic evidence of residual invasive tumour in all resected
    specimens of the breast and axilla (ypT0/is ypN0) in all patients
    • pCR is defined as no microscopic evidence of residual invasive tumour in all resected specimens of the breast and axilla (ypT0/is ypN0) in patients with or without PIK3CA/AKT1/PTEN genetic alterations

    Biological:
    2-fold increase in GzmB+ CD8+ T cell levels from baseline to the end of each treatment
    phase
    Clínicos:
    •La RCp se define como la ausencia de signos microscópicos de tumor infiltrante residual en todas las muestras resecadas de la mama y la axila (ypT0/is ypN0) en todas las pacientes.
    •La RCp se define como la ausencia de signos microscópicos de tumor infiltrante residual en todas las muestras resecadas de la mama y la axila (ypT0/is ypN0) en todas las pacientes, con o sin alteraciones genéticas de PIK3CA/AKT1/PTEN.
    Biológico:
    Multiplicación por 2 de los niveles de linfocitos T CD8+ GzmB+ desde el periodo basal hasta el final de cada fase de tratamiento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the time of definitive surgery following completion of study treatment.
    Al momento de la cirugía definitiva después de la finalización del tratamiento del estudio.
    E.5.2Secondary end point(s)
    Secondary:
    • Objective response rate (ORR) as assessed by RECIST 1.1 principles, defined as percentage of subjects with best overall response of complete response (CR) or partial response (PR) in the relevant analysis population
    • ORR
    • Status and changes of the biomarkers listed below in pre- and end-of treatment tumour
    and/or blood samples: immune phenotyping, CD8, PD-L1 & MHC-I, immune infiltrates (IFNg gene signature expression)
    • IEFS, defined as the time from randomisation to date of first treatment failure that is invasive loco-regional or distant recurrence or new invasive cancer or death from any cause. IEFS is further detailed according to the standardized STEEP system definition as one of the following [13]:
    o Distant recurrence: metastatic disease-breast cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer o Death attributable to any cause, including breast cancer, non-breast
    cancer, or unknown cause
    o Ipsilateral invasive breast tumour recurrence (IIBTR): invasive breast
    cancer involving the same breast parenchyma as the original primary
    o Regional invasive breast cancer recurrence: Invasive breast cancer in the
    axilla, regional lymph nodes, chest wall, and skin of the ipsilateral breast. o Contralateralinvasivebreastcancer
    o Secondprimarynon-breastinvasivecancer
    • DEFS, defined as the time from randomisation to the date of first distant recurrence or death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. Distant recurrence is defined as metastatic disease-breast cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer.
    • OS, defined as time from randomisation to death of any cause
    • Assessment of mean changes in function and disease/treatment-related symptoms in
    all scales of the EORTC QLQ-C30 by treatment arm
    • Health utility assessment as measured by the EQ-5D during the study for health economic evaluations
    • Incidence, nature and severity of adverse events with severity determined according to CTCAE v4.03.
    •La tasa de respuesta objetiva (TRO) evaluada según los criterios RECIST 1.1, definida como el porcentaje de sujetos con una mejor respuesta global de respuesta completa (RC) o respuesta parcial (RP) en la población de análisis correspondiente.
    •TRO.
    •Estado y variaciones de los biomarcadores enumerados a continuación en muestras tumorales y/o de sangre obtenidas antes y después del tratamiento: inmunofenotipado, CD8, PD-L1 y MHC-I, inmunoinfiltrados (expresión de la firma genética del IFN).
    •La SLEI, definida como el tiempo transcurrido desde la aleatorización hasta la fecha del primer fracaso del tratamiento por recidiva locorregional infiltrante o metástasis a distancia o un nuevo cáncer infiltrante o la muerte por cualquier causa. La SLEI se detalla aún más según la definición normalizada del sistema STEEP como una de las siguientes [13]:
    o Metástasis a distancia: cáncer de mama metastásico que se ha confirmado mediante biopsia o se ha diagnosticado clínicamente como cáncer de mama infiltrante recidivado.
    o Muerte debida a cualquier causa, como el cáncer de mama, un cáncer distinto del de mama o una causa desconocida.
    o Recidiva ipsilateral del tumor mamario infiltrante (IIBTR): cáncer de mama infiltrante que afecta al mismo parénquima mamario que el cáncer primario original.
    o Recidiva regional del cáncer de mama infiltrante: Cáncer de mama infiltrante en la axila, los ganglios linfáticos regionales, la pared torácica y piel de la mama ipsilateral.
    o Cáncer de mama invasivo contralateral.
    o Segundo cáncer invasivo primario distinto de cáncer de mama.
    •SLED, definida como el tiempo transcurrido desde la aleatorización hasta la fecha de la primera metástasis a distancia o la muerte atribuible a cualquier causa, incluidos el cáncer de mama, un cáncer distinto del de mama o una causa desconocida. La metástasis a distancia se define como un cáncer de mama metastásico que se ha confirmado mediante biopsia o se ha diagnosticado clínicamente como cáncer de mama infiltrante recidivado.
    •SG, definida como el tiempo transcurrido desde la aleatorización hasta la muerte por cualquier causa.
    •Evaluación de la media de los cambios en la función y los síntomas relacionados con la enfermedad/el tratamiento en todas las escalas del cuestionario QLQ-C30 de la EORTC por grupo de tratamiento.
    •Evaluación de utilidad médica medida por el cuestionario EQ-5D durante el estudio de evaluaciones de economía de la salud.
    •Incidencia, naturaleza y severidad de los acontecimientos adversos, determinándose la intensidad según la versión 4.03 de los CTCAE.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. As indicated per local guidelines- after completion of neoadjuvant treatment and prior to surgery (min 3 weeks after last dose, max 1 day prior to surgery), or sooner if clinically indicated. Thereafter, annual mammogram (or MRI of the breast) for 5 years, unless patient had bilateral mastectomy.
    2. As per endpoint 1
    3. Pre- during and post-treatment samples
    4. Same as endpoint 1
    5. Same as endpoint 1
    6. Death at any timepoint
    7 & 8. Baseline, C3, 5, 7, pre-surgery, every 4mos Yr 1&2 and 6monthly Yr 3 to 5
    9. From consent to 135 days after last dose of atezolizumab.
    1. Según guías locales, después de completar el tratamiento neoadyuvante y antes de la cirugía (mínimo 3 semanas después de la última dosis, máximo 1 día antes de la cirugía), o antes en caso de estar clínicamente indicado. A partir de entonces, una mamografía anual (o MRI de la mama) durante 5 años, a menos que el paciente se haya sometido a una mastectomía bilateral.
    2. Según variable 1
    3. Muestras previas y posteriores al tratamiento.
    4. Igual que variable 1
    5. Igual que variable 1
    6. Muerte en cualquier momento
    7 y 8. Momento basal, C3, 5, 7, antes de la cirugía, cada 4 meses durante los años 1&2 y cada 6 meses durante los años 3 a 5
    9. Desde el consentimiento hasta 135 días después de la última dosis de atezolizumab.
    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 Yes
    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 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) Yes
    E.8.2.2Placebo No
    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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA39
    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 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
    The end of study is defined as last patient last data collection, which for the primary and secondary analysis is expected to occur approximately by the LPLV time point allow for the centralisation of tumour samples and biomarker analysis. All exploratory research will be completed by LPLV
    El final del estudio se define como la última recopilación de datos del último paciente, que se espera que ocurra para el análisis primario y secundario aproximadamente en el momento de la última vista del último paciente (UVUP), para permitir la centralización de las muestras de tumores y el análisis de biomarcadores. Toda la investigación exploratoria se completará en el momento de la UVUP.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months1
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 142
    F.4.2.2In the whole clinical trial 142
    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, this is a neo-adjuvant study. After completion of study treatment, participants will undergo definitive local surgery (mastectomy or breast conserving surgery) with appropriate axillary sampling of ipsilateral nodes within 3 to 6 weeks after the last dose of neoadjuvant treatment.Participants will be followed up for 5 years after surgery.
    Ninguno, este es un estudio neo-adyuvante. Después de completar el tratamiento del estudio, los participantes se someterán a una cirugía local definitiva (mastectomía o cirugía de conservación de la mama) con un muestreo axilar apropiado de los ganglios ipsilaterales dentro de las 3 a 6 semanas posteriores a la última dosis de tratamiento neoadyuvante. Los participantes deberán realizar un seguimiento durante 5 años después de la cirugía.
    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 Decision2019-05-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-24
    P. End of Trial
    P.End of Trial StatusOngoing
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