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    Summary
    EudraCT Number:2015-003612-20
    Sponsor's Protocol Code Number:C31006
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-04-20
    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 number2015-003612-20
    A.3Full title of the trial
    An Open-Label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With Fulvestrant in Women With ER-Positive/HER2-Negative Advanced or Metastatic Breast Cancer That Has Progressed During or After Aromatase Inhibitor Therapy.
    Estudio de fase 2, abierto, de MLN0128 (un inhibidor de TORC1/2) en combinación con fulvestrant en mujeres con cáncer de mama avanzado o metastásico ER positivo/HER2 negativo que hayan progresado durante o después de un tratamiento con inhibidores de la aromatasa.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MLN0128 in Combination With Fulvestrant in Women With Advanced or Metastatic Breast Cancer After Aromatase Inhibitor Therapy.
    MLN0128 en combinación con Fulvestrant en mujeres con cáncer de mama avanzado o metastásico después de un tratamiento con inhibidores de la aromatasa.
    A.4.1Sponsor's protocol code numberC31006
    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 SponsorMillennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMillennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGEICAM (Grupo Español de Investigación en Cáncer de Mama)
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressAv de los Pirineos 7, 1º-3
    B.5.3.2Town/ citySan Sebastián de los Reyes/Madrid
    B.5.3.3Post code28703
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491916592870
    B.5.5Fax number+3491916592870
    B.5.6E-mailinicio_ensayos@geicam.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 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 nameMLN0128
    D.3.2Product code TAK-228
    D.3.4Pharmaceutical form Capsule
    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 INNTAC-228
    D.3.9.1CAS number 1224844-38-5
    D.3.9.2Current sponsor codeMLN0128
    D.3.9.4EV Substance CodeSUB79236
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameMLN0128
    D.3.2Product code TAK-228
    D.3.4Pharmaceutical form Capsule
    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 INNTAC-228
    D.3.9.1CAS number 1224844-38-5
    D.3.9.2Current sponsor codeMLN0128
    D.3.9.4EV Substance CodeSUB79236
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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 nameMLN0128
    D.3.2Product code TAK-228
    D.3.4Pharmaceutical form Capsule
    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 INNTAC-228
    D.3.9.1CAS number 1224844-38-5
    D.3.9.2Current sponsor codeMLN0128
    D.3.9.4EV Substance CodeSUB79236
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 RoleComparator
    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 Faslodex
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca UK 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 nameFaslodex
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFaslodex
    D.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    Advanced or Metastatic Breast Cancer.
    Cáncer de mama avanzado o metastásico.
    E.1.1.1Medical condition in easily understood language
    Patients with Advanced or Metastatic Breast Cancer.
    Pacientes con cáncer de mama avanzado o metastásico.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10006187
    E.1.2Term 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 compare the PFS of patients treated with the combination of fulvestrant+daily MLN0128 versus patients treated with single-agent fulvestrant.
    - To compare the PFS of patients treated with the combination of fulvestrant+weekly MLN0128 versus patients treated with single-agent fulvestrant.
    - Comparar la SLP de las pacientes tratadas con la combinación de fulvestrant + MLN0128 diario frente a aquellas tratadas con fulvestrant en monoterapia.
    - Comparar la SLP de las pacientes tratadas con la combinación de fulvestrant + MLN0128 semanal frente a aquellas tratadas con fulvestrant en monoterapia.
    E.2.2Secondary objectives of the trial
    - To compare secondary efficacy endpoints in patients treated with the combination of
    fulvestrant+daily MLN0128 versus patients treated with single-agent fulvestrant.
    - To compare secondary efficacy endpoints in patients treated with the combination of
    fulvestrant+weekly MLN0128 versus patients treated with single-agent fulvestrant.
    - To assess the safety and tolerability of the combination of fulvestrant+MLN0128.
    - To collect plasma concentration-time data with sparse PK sampling (combination
    fulvestrant+MLN0128 treatment arms [Arm B and Arm C] only), to contribute to future
    population PK analysis.
    - Comparar las variables de eficacia secundaria de las pacientes tratadas con la combinación de fulvestrant + MLN0128 diario frente a aquellas tratadas con fulvestrant en monoterapia.
    - Comparar las variables de eficacia secundaria de las pacientes tratadas con la combinación de fulvestrant + MLN0128 semanal frente a aquellas tratadas con fulvestrant en monoterapia.
    - Evaluar la seguridad y la tolerabilidad de la combinación de fulvestrant+MLN0128.
    - Recoger datos de concentración plasmática-tiempo con muestreo de farmacocinética (PK) (solo los brazos de tratamiento de combinación de fulvestrant+MLN0128 [brazo B y brazo C]) para contribuir a análisis farmacocinéticos poblacionales en el futuro.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Female patients aged 18 years or older who are postmenopausal. Postmenopausal is defined
    as:
    - Aged > or = 55 years and 1 year or more of natural amenorrhea prior to the Screening visit, or
    - Aged <55 years and 1 year or more of amenorrhea prior to the Screening visit, with a follicle-stimulating hormone level >40 mIU/mL and an estradiol level of <20 pg/mL, or
    - Surgical menopause with bilateral oophorectomy.
    Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone
    agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.
    2. Histologically proven diagnosis of breast cancer with evidence of metastatic disease or
    locoregional recurrence, not amenable to resection or radiation therapy with curative intent.
    3. Histological confirmation and documentation of ER-positive status (?1% positive stained cells) by local laboratory testing utilizing an assay consistent with local standards.
    4. Histological or cytological confirmation and documentation of HER2-negative status by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College
    of American Pathologists (CAP) Clinical Practice Guideline update.
    5. Measureable disease defined as:
    - At least 1 extra-osseous lesion that can be accurately measured in at least 1 dimension. The lesion must measure ?20 mm with conventional imaging techniques or ?10 mm with spiral CT or MRI, or
    - Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as defined above.
    Note: Patients with sclerotic/osteoblastic bone lesions only, in the absence of measurable disease, are not eligible.
    6. PD during prior AI therapy defined as:
    - Progression during or within 12 months after completion or discontinuation of adjuvant therapy or
    - Progression during or within 1 month after the end of therapy in the metastatic setting.
    Note: AI is not required to be the most recent therapy, but progression on AI and
    progression on most recent therapy are both required for eligibility.
    7. Patients who have a history of brain metastasis are eligible for the study provided that all of the following criteria are met:
    - Brain metastases have been treated.
    - No evidence of PD for 3 months before the first dose of study drug.
    - No hemorrhage after treatment.
    - Off dexamethasone treatment for ?4 weeks before the first dose of study drug.
    - No ongoing requirement for dexamethasone or anti-epileptic drugs.
    8. ECOG performance status of 0 or 1 (refer to Appendix D).
    9. Clinical laboratory values as specified below within 4 weeks before the first dose of study drug:
    - Bone marrow reserve consistent with absolute neutrophil count (ANC) ?1.5x10^9/L;
    platelet count ?100x10^9/L; hemoglobin (Hgb) ?9 g/dL.
    - Total bilirubin ?1.5 x the upper limit of the normal range (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ?2.5xULN (?5xULN if liver metastases are present).
    - Creatinine clearance ?40 mL/min based on Cockcroft-Gault estimate (refer to
    Appendix E) or based on a 12- or 24-hour urine collection.
    - Fasting serum glucose ?130 mg/dL and fasting triglycerides ?300 mg/dL.
    10. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.
    11. Voluntary written consent must be given by the patient (or the patient?s legally acceptable representative) before performance of any study-related procedure that is not part of standard medical care, with the understanding that consent may be withdrawn at any time without prejudice to the patient?s future medical care.
    1. Pacientes mujeres ? 18 años de edad que sean postmenopáusicas. Las mujeres postmenopáusicas se definen como:
    ? 55 años de edad y que hayan pasado ? 1 año de amenorrea natural antes de la visita de selección, o
    < 55 años de edad y que hayan pasado ? 1 año de amenorrea natural antes de la visita de selección, con un nivel de hormona foliculoestimulante > 40 mIU/ml y un nivel de estradiol < 20 pg/ml, o
    que hayan sido intervenidas con ooforectomía bilateral.
    Nota: el tratamiento o la radiación de ovarios con un agonista de la hormona luteinizante liberadora de hormonas (acetato de goserelina o acetato de leuprolide) no están permitidos para la inducción de la supresión ovárica.
    2. Diagnóstico histológicamente confirmado de cáncer de mama con evidencia de metástasis o recurrencia locorregional que no sea susceptible de resección o radioterapia con fines curativos.
    3. Confirmación histológica y documentación del estado de RE positivo (? 1 % de células positivas con tinción) mediante pruebas analíticas locales utilizando un análisis que cumpla con las normas locales.
    4. Confirmación histológica o citológica y documentación del estado HER2 negativo mediante pruebas analíticas locales utilizando los criterios de la actualización de las guás de práctica clínica de la American Society of Oncology (ASCO)/ College of American Pathologists (CAP).
    5. Enfermedad medible definida como:
    - Al menos 1 lesión extraósea que puede medirse de forma precisa en por lo menos una dimensión. La lesión debe medir ? 20 mm con técnicas de diagnóstico por imagen convencionales o ? 10 mm con TC o RM helicoidal, o
    - Lesiones óseas (líticas o mixtas [líticas más escleróticas]) en ausencia de otras enfermedades medibles anteriormente definidas.
    Nota: las pacientes solo con lesiones óseas escleróticas/osteoblásticas no son elegibles en ausencia de otra enfermedad medible.
    6. PD (progresión) durante o después un tratamiento previo con IA se define como:
    - Progresión durante o en los 12 meses posteriores a la finalización o retirada del tratamiento adyuvante o
    - Progresión durante o en el mes posterior a la retirada del mismo en caso de enfermedad metastásica.
    Nota: no es necesario que los IA sean el tratamiento más reciente, aunque la progresión tras recibir IA y la progresión tras recibir el tratamiento más reciente son necesarias para la elegibilidad.
    - Las pacientes con antecedentes de metástasis cerebral son elegibles para participar en el estudio siempre que se cumplan todos los criterios siguientes:
    - Que las metástasis cerebrales se hayan tratado.
    - Que no muestren signos de PD durante ? 3 meses antes de la primera dosis del fármaco del estudio.
    - Que no sufran hemorragias después del tratamiento.
    - Que no hayan recibido tratamiento con dexametasona durante ? 4 semanas antes de la primera dosis del fármaco del estudio.
    - Que no exista ningún requisito para continuar con dexametasona o fármacos antiepilépticos.
    8. Estado funcional del ECOG de 0 o 1.
    9. Cualquiera de los siguientes valores de laboratorio clínico durante las 4 semanas anteriores a la primera dosis del fármaco del estudio:
    - Reserva de médula ósea con un recuento absoluto de neutrófilos (RAN) ? 1,5 x 10^9/l; recuento de plaquetas ?100 x 10^9/l; hemoglobina (Hb) ? 9 g/dl.
    - Bilirrubina total ? 1,5 x el límite superior de normalidad (LSN), aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ? 2,5 x LSN (? 5 x LSN si existen metástasis hepáticas).
    - Aclaramiento de la creatinina ? 40 ml/min calculado mediante la fórmula de Cockcroft-Gault o basándose en una recogida de orina de 12 o 24 horas.
    - Glucosa sérica en ayunas ? 130 mg/dl y triglicéridos en ayunas ? 300 mg/dl.
    10. Capacidad de tragar medicamentos orales, voluntad de realizar la profilaxis de la mucositis y acceso venoso adecuado para la recogida de muestras de sangre necesarias para el estudio.
    11. La paciente (o el representante legal de la paciente) debe otorgar su consentimiento voluntario por escrito antes de realizar cualquier procedimiento relacionado con el estudio que no forme parte de la práctica habitual, con el entendimiento de que el consentimiento se puede revocar en cualquier momento sin que ello comporte ningún perjuicio a la asistencia médica futura de la paciente.
    E.4Principal exclusion criteria
    1. Prior therapy with mTOR, PI3K, or dual PI3K-mTOR inhibitors, AKT inhibitors, or
    fulvestrant.
    2. Prior treatment with >1 line of chemotherapy for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent.
    3. Experienced recurrent or PD on >2 endocrine therapies for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent.
    4. Life-threatening metastatic visceral disease (defined as extensive hepatic involvement or symptomatic pulmonary lymphangitic spread). Patients with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not compromised as a result of disease.
    5. Other clinically significant comorbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could
    compromise the patient?s participation in the study.
    6. History of any of the following within the last 6 months before the first dose of study drug:
    - Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.
    - Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures.
    - Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
    - Placement of a pacemaker for control of rhythm.
    - New York Heart Association Class III or IV heart failure (see Appendix F).
    - Pulmonary embolism.
    7. Significant active cardiovascular or pulmonary disease, including:
    - Uncontrolled hypertension (ie, either systolic blood pressure >180 mm Hg or diastolic blood pressure >95 mm Hg).
    - Pulmonary hypertension.
    - Uncontrolled asthma or oxygen saturation <90% by arterial blood gas analysis or pulse
    oximetry on room air.
    - Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement.
    Medically significant (symptomatic)bradycardia.
    - History of arrhythmia requiring an implantable cardiac defibrillator.
    - Baseline prolongation of QTc (eg, repeated demonstration of QTc interval >480 ms, or
    history of congenital long QT syndrome, or torsades de pointes).
    8. Diagnosed with or treated for another malignancy within 2 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
    9. Prior anticancer therapy or other investigational therapy within 2 weeks before the first dose of study drug.
    10. Chronic concomitant therapy with bone-targeting agents (eg, bisphos, denosumab) for the prevention of bone metastases. Concomitant treatment with bone-targeting agents is permitted for treatment of osteoporosis or management of existing bone metastases if initiated at least 4 weeks before the first dose of study drug.
    11. Treatment with strong cytochrome P450 (CYP) 3A4, CYP2C9, and/or CYP2C19 inhibitors
    and/or inducers within 1 week before the first dose of study drug (see Appendix G).
    12. Initiation of treatment with systemic corticosteroids (either IV or oral steroids) within 1 week before the first dose of study drug. However, inhalers and low-dose replacement therapy are allowed.
    13. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128.
    14. Poorly controlled diabetes mellitus defined as hemoglobin A1c (glycosylated hemoglobin; HbA1c) >7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be eligible if all other inclusion/exclusion criteria are met.
    15. Known human immunodeficiency virus infection.
    1. Tratamiento previo con inhibidores mTOR, PI3K o PI3K-mTOR, inhibidores AKT o fulvestrant.
    2. Tratamiento previo con > 1 línea de quimioterapia para el cáncer de mama metastásico o para recurrencia locorregional que no sea susceptible de resección o radioterapia con fines curativos.
    3. Pacientes que hayan experimentado recurrencia o PD tras recibir > 2 tratamientos endocrinos para cáncer de mama metastásico o para recurrencia locorregional que no sea susceptible de resección o radioterapia con fines curativos.
    4. Enfermedad visceral metastásica potencialmente mortal (definida como una afectación hepática extensa o linfangitis pulmonar sintomática). Las pacientes con metástasis parenquimatosas pulmonares moderadas son elegibles, siempre que su función respiratoria no se vea afectada a causa de la enfermedad.
    5. Otras comorbilidades clínicamente significativas, como enfermedad pulmonar no controlada, enfermedad activa del sistema nervioso central, infección activa, o cualquier otra enfermedad que ponga en peligro la participación de la paciente en el estudio.
    6. Antecedentes de cualquiera de los siguientes durante los 6 meses anteriores a la primera dosis del fármaco del estudio:
    - Acontecimiento de isquemia miocárdica, incluida angina que requiera tratamiento y procedimientos de revascularización arterial.
    - Acontecimiento cerebrovascular isquémico, incluido accidente isquémico transitorio y revascularización arterial.
    - Necesidad de soporte inotrópico (salvo digoxina) o arritmia cardíaca grave (no controlada) (incluido aleteo/fibrilación auricular, fibrilación ventricular o taquicardia ventricular).
    - Implantación de marcapasos para controlar el ritmo.
    - Insuficiencia cardíaca de clase III o IV de la New York Heart Association.
    - Embolia pulmonar.
    7. Enfermedad cardiovascular o pulmonar activa significativa, incluida:
    - Hipertensión no controlada (es decir, presión arterial sistólica > 180 mmHg o diastólica > 95 mmHg).
    - Hipertensión pulmonar.
    - Asma no controlada o saturación de oxígeno < 90 % mediante gasometría arterial u oximetría de pulso a temperatura ambiente.
    - Valvulopatía significativa; regurgitación o estenosis severa mediante diagnóstico por imagen independiente del control de síntomas con intervención médica; o antecedentes de recambio valvular.
    - Bradicardia clínicamente significativa (sintomática).
    - Antecedentes de arritmia que requiere un desfibrilador cardíaco implantable.
    - Prolongación de QTc basal (p. ej., demostración repetida del intervalo de QTc > 480 ms, o antecedentes de síndrome de QT largo congénito, o Torsade de Pointe).
    8. Diagnóstico o tratamiento de otro tumor maligno durante los 2 años anteriores a la primera dosis del fármaco del estudio, o diagnóstico previo de otro tumor maligno y signos de enfermedad residual. Las pacientes con cáncer de piel no melanomatoso o carcinoma in situ de cualquier tipo no quedan excluidas si se han sometido a una resección completa.
    9. Tratamiento previo contra el cáncer u otro tratamiento en investigación durante las 2 semanas anteriores a la primera dosis del fármaco del estudio.
    10. Tratamiento crónico concomitante con fármacos dirigidos a los huesos (p. ej., bifosfonatos, denosumab) para la prevención de las metástasis óseas. El tratamiento concomitante con fármacos dirigidos a los huesos está permitido para el tratamiento de la osteoporosis o el control de las metástasis óseas existentes si se ha iniciado al menos 4 semanas antes de la primera dosis del fármaco del estudio.
    11. Tratamiento con inhibidores o inductores potentes del citocromo P450 (CYP) 3A4, CYP2C9 o CYP2C19 durante la semana anterior a la primera dosis del fármaco del estudio.
    12. Inicio de un tratamiento con corticosteroides sistémicos (esteroides i.v. u orales) durante la semana anterior a la primera dosis del fármaco del estudio. Sin embargo, están permitidos los inhaladores y la terapia sustitutiva en dosis bajas.
    13. Manifestaciones de absorción insuficiente debido a una cirugía gastrointestinal (GI) previa, enfermedad GI o por algún motivo desconocido que pueda alterar la absorción de MLN0128.
    14. Diabetes mellitus mal controlada definida como hemoglobina A1c (hemoglobina glucosilada HbA1c) > 7 %; las pacientes con antecedentes de intolerancia transitoria a la glucosa a causa de la administración de corticosteroides pueden ser elegibles si cumplen todos los demás criterios de inclusión/exclusión.
    15. Infección conocida por el virus de la inmunodeficiencia humana.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is:
    - PFS.
    La variable principal de este estudio es la SLP.
    E.5.1.1Timepoint(s) of evaluation of this end point
    A final analysis of PFS will be performed
    after the required number of events has been observed which is expected approximately 20 months after the first patient is randomized.
    E.5.2Secondary end point(s)
    - Overall survival (OS).
    - Time to progression (TTP).
    - Objective response rate (ORR); defined as CR+PR per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [1].
    - CBR; defined as CR+PR+SD with SD of any duration, and CBR with SD duration of at least
    6 months.
    - The number and percentage of patients with treatment-emergent AEs.
    Las variables secundarias de este estudio son la supervivencia global (SG), el tiempo hasta la progresión (TP), la tasa de respuesta objetiva (TRO), la tasa de beneficio clínico (TBC) con enfermedad estable (EE) de cualquier duración, la TBC con EE de al menos 6 meses de duración y el número y porcentaje de pacientes con AA causados por el tratamiento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    ORR is defined as the proportion of patients who achieve a best response of complete response (CR) or partial response (PR) according to RECIST 1.1 criteria [1]. CBR is defined as the proportion of patients who achieve a best response of CR, PR, or SD. The CBR will also be presented for a best response of CR, PR, and SD of at least 6 months.
    TTP is defined as the time from the date of randomization to the date of first documentation of progression. For a
    patient whose disease has not progressed, TTP will be censored at the last response assessment that is SD or better.
    TTP will be analyzed using similar methods as the primary endpoint of PFS.
    AEs will be collected throughout the study.
    La TRO se define como la proporción de pacientes con una mejor respuesta completa (RC) o parcial (RP), según los criterios RECIST v1.1 [1]. La TBC se define como la proporción de pacientes con una mejor respuesta de RC, RP o EE. También se presentará la TBC de una mejor respuesta de CR, PR y EE de al menos 6 meses. El TP se define como el tiempo desde la fecha de aleatorización hasta la fecha de la primera progresión documentada. En las pacientes cuya enfermedad no haya progresado, se censurará el TP en la última evaluación de la respuesta que sea EE o un valor mejor. El TP se analizará con métodos similares a los de la variable principal SLP.
    Los AAs serán recogidos durante todo el estudio.
    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 Yes
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned25
    E.8.5The trial involves multiple Member States No
    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
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Última visita de la última paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    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: 153
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 153
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state76
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 76
    F.4.2.2In the whole clinical trial 153
    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.
    Ninguno
    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 Decision2016-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-19
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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