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    Summary
    EudraCT Number:2013-002403-34
    Sponsor's Protocol Code Number:009175QM
    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:2014-03-19
    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 number2013-002403-34
    A.3Full title of the trial
    A Randomized Phase II Study of Fulvestrant in Combination with the dual mTOR Inhibitor AZD2014 or Everolimus or Fulvestrant alone in Estrogen Receptor Positive Advanced or Metastatic Breast Cancer.
    Estudio aleatorizado de fase II de fulvestrant en combinación con el inhibidor dual de mTOR, AZD2014 o bien con everolimus o fulvestrant en monoterapia para el tratamiento del cáncer de mama avanzado o metastásico con receptores de estrógenos positivos.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized Phase II study comparing treatment combinatons of Fulvestrant and AZD2014, Fulvestrant and Everolimus or Fulvestrant alone for patients with advanced or metastatic breast cancer.
    Comparación de la eficacia de 3 grupos aleatorizados de fulvestrant + AZD2014 frente a fulvestrant + everolimus frente a fulvestrant en monoterapia en pacientes con cáncer de mama avanzado o metastásico con receptores de estrógenos positivos
    A.3.2Name or abbreviated title of the trial where available
    MANTA
    MANTA
    A.4.1Sponsor's protocol code number009175QM
    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 supportAstraZeneca
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQueen Mary University of London
    B.5.2Functional name of contact pointCentre for Experimental Cancer Medi
    B.5.3 Address:
    B.5.3.1Street AddressBarts Cancer Institute,Old Anatomy Building, Charterhouse Square,
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeEC1M 6BQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4402078828490
    B.5.5Fax number+4402078825958
    B.5.6E-mailMANTA@qmcr.qmul.ac.uk
    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.3.2Product code AZD2014
    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 INN3-[2,4-Bis((3S)-3-methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide
    D.3.9.1CAS number 1009298-59-2
    D.3.9.2Current sponsor codeAZD2014
    D.3.9.3Other descriptive nameAZD2014
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.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 Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameEverolimus
    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 INN.
    D.3.9.1CAS number 159351-69-6
    D.3.9.2Current sponsor code.
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Estrogen receptor positive advanced or metastatic breast cancer.
    cáncer de mama avanzado o metastásico con receptores de estrógenos positivos
    E.1.1.1Medical condition in easily understood language
    Breast Cancer
    Cancer de Mama
    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
    The main aims of this study are to:
    ? Determine whether dual inhibition of mTORC 1 and mTORC2 with AZD2014 will increase the antitumour activity of endocrine treatment with fulvestrant in ER positive advanced or metastatic breast cancer.
    ? Determine whether inhibition of both mTORC 1 and mTORC2 using AZD2014 will have superior antitumour activity compared to inhibition of mTORC1 alone with everolimus, when combined with fulvestrant.
    ? Explore whether additional efficacy is likely to be present in a subgroup with PI3K pathway activation for whom it is hypothesised that there will be greater sensitivity to mTOR inhibitors
    ? Characterize the patient population who might benefit from fulvestrant plus AZD2014 to identify potential predictors of sensitivity
    The primary objectives of this study are to:
    ? Estimate the clinical benefit (CB) of fulvestrant+AZD2014 relative to fulvestrant+everolimus or fulvestrant alone, as measured by investigator assessed progression free survival (PFS)
    Los objetivos principales de este estudio son los siguientes:
    -Determinar si la inhibición doble de mTORC1 y mTORC2 con AZD2014 aumentará la actividad antitumoral del tratamiento endocrino con fulvestrant en el cáncer de mama avanzado o metastásico con RE positivo.
    -Determinar si la inhibición de mTORC 1 y mTORC2 utilizando AZD2014 tendrá actividad antitumoral en comparación con la inhibición de mTORC1 solo con everolimus, cuando se combina con fulvestrant
    -Explorar si es probable que se consiga una eficacia adicional en un subgrupo con activación de la vía de PI3K para el que se formula la hipótesis de que tendrá una mayor sensibilidad a los inhibidores de mTOR.
    -Caracterizar a la población de pacientes que pueden beneficiarse de fulvestrant más AZD2014 para identificar posibles factores de predicción de la sensibilidad.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to:
    ? Estimate CB of fulvestrant+AZD2014 relative to other arms by PFS and an IRF.
    ? Assess clinical activity, as measured by response rate (RECIST 1.1), CB rate and duration of response, of fulvestrant+AZD2014 relative to other arms.
    ? Establish the safety and tolerability of fulvestrant+AZD2014 relative to other arms.
    ? Estimate the overall survival benefit of fulvestrant+AZD2014 relative to other arms.
    ? Investigate the effects of fulvestrant+AZD2014 or everolimus on bone turnover biomarkers.
    ? Compare the differences in patient reported outcomes as measured by the Functional Assessment of Cancer Therapy General scale together with the Breast-AntiA and Endocrine Symptom subscales.
    ? Investigate pharmacokinetics of AZD2014 in patients coadministered with fulvestrant.
    ? Determine the minimum plasma concentration at steady state in breast cancer patients of fulvestrant alone and when administered in combination with AZD2014/everolimus.
    ?Evaluar el beneficio clínico de fulvestrant + AZD2014 versus fulvestrant + everolimus o fulvestrant en monoterapia, medido por la supervivencia sin progresión (SSP).
    ?Evaluar la actividad clínica, por la respuesta (RECIST 1.1), el beneficio clínico, sus duraciónes de fulvestrant + AZD2014 versus fulvestrant + everolimus o fulvestrant en monoterapia.
    ?Determinar la seguridad, tolerabilidad y supervivencia global de fulvestrant + AZD2014 frente a fulvestrant + everolimus o fulvestrant en monoterapia.
    ?Investigar los efectos de fulvestrant +/- AZD2014 o everolimus en biomarcadores de la rotación ósea.
    ?Comparar las pacientes, medidas con la escala General (FACT-G) junto con las subescalas de mama, anti-A y síntomas endocrinos (FACT-B-Anti-A-ES).
    ?Investigar la farmacocinética de AZD2014 conjuntamente con fulvestrant.
    ?Determinar la concentración plasmática mínima al equilibrio de fulvestrant en monoterapia o administrado en combinación con AZD2014 o everolimus.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent prior to admission to this study.
    2. Women, age ? 18 years.
    3. Histologically confirmed breast cancer.
    4. Metastatic or locally recurrent disease? locally recurrent disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential downstaging with study treatment are not eligible).
    5. Patients must have:
    a. at least one lesion, not previously irradiated, that can be measured accurately at baseline as ? 10mm in the longest diameter (except lymph nodes which must have short axis ? 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, or
    b. lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above? patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible
    6. Radiological or clinical evidence of recurrence or progression
    7. ER positive disease, defined as tumour cells being positive for ER with ?1% of tumour cells positive for ER on IHCor IHC score (Allred) of ?3
    8. HER2 negative disease with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH.
    9. Formalin fixed, paraffin embedded tumour sample from the primary and/or recurrent cancer must be available for central testing
    10. Postmenopausal women. Women will be considered postmenopausal if they meet one of the following criteria:
    a. Age ?50 years and 1 year or more of amenorrhea
    b. Age <50 years and 1 year or more of amenorrhea, with an estradiol assay <20pg/mL
    c. Age <50 with prior hysterectomy but intact ovaries with an estradiol assay <20pg/mL
    d. Status after bilateral oophorectomy (?28 days prior to first study treatment)
    Note: Ovarian radiation or treatment with a luteinizing hormonereleasing
    hormone (LHRH) agonist (goserelin acetate
    or leuprolide acetate) is not permitted for induction of ovarian suppression.
    11. Disease refractory to aromatase inhibitors (AI), defined as
    a. Disease recurrence while on, or within 12 months of end of adjuvant treatment with letrozole, anastrozole, or exemestane
    b. Progression while on, or within one month of end of letrozole, anastrozole or exemestane treatment for locally advanced or metastatic Breast Cancer.
    Note: Any number of lines of hormonal therapy before or after AI therapy is allowed.
    Note: Letrozole, anastrozole or exemestane do not have to be the last treatment prior to randomisation.
    12. Haematologic and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to randomisation
    a. ANC ? 1500 cells/?l, haemoglobin ? 9g/dl, and platelet count ?100000/?l
    b. Serum Creatinine <1.5 times ULN concurrent with creatinine clearance ?50mL/min (measured or calculated by Cockcroft and Gault equation), confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN
    c. Bilirubin level < 1.5 x ULN if no demonstrable liver metastases or < 3 times ULN in the presence of liver metastases
    d. AST or ALT <2.5 x ULN
    e. International normalized ratio (INR) <1.5 and activated partial thromboplastin time (aPTT) <1.5 x ULN? for patients requiring therapeutic anticoagulation therapy, a stable INR ?2.5 x ULN is required to mitigate potential bleeding
    f. No Clinically relevant and treatment resistant abnormalities in potassium, sodium, calcium (corrected for plasma albumin) or magnesium
    g. Fasting serum cholesterol ? 300 mg/dl or 7.75 mmol/L and fasting triglycerides ? 2.5 ×ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved
    13. ECOG performance status 0-2
    14. Nonchildbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had a hysterectomy, bilateral oophorectomy, bilateral tubular ligation or is postmenopausal (total cessation of menses for ? 1 year? if the patient is of childbearing potential, she must have a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use
    adequate contraception (for example, intrauterine device [IUD], birth control pills unless clinically contraindicated, or barrier device) beginning 2 weeks before the first dose of investigational product and for 8 weeks after the final dose of investigational product.
    ?Consentimiento informado por escrito
    ?Mujeres ? 18 años de edad
    ?Cáncer de mama confirmado histológicamente
    ?Enfermedad metastásica o localmente recurrente; la enfermedad localmente recurrente no puede ser resecable quirúrgicamente con intenciones curativas (las pacientes que se consideren candidatas adecuadas para técnicas quirúrgicas o ablativas después de una posible mejora del estadio con el tratamiento del estudio no serán elegibles).
    ?El paciente debe tener:
    o al menos una lesión, no previamente irradiada, que se pueda medir con precisión al inicio y sea ? 10 mm de diámetro mayor (excepto los ganglios linfáticos que deben ser de ? 15 mm de eje corto) mediante tomografía computarizada (TC) o por imagen de resonancia magnética (MRI), adecuadas para las mediciones repetidas precisas, o
    o lesiones óseas líticas o mixtas (lítico + esclerótica) en ausencia de enfermedad medible como se definió anteriormente; las pacientes con lesiones óseas escleróticas / osteoblástica no son elegibles en ausencia de enfermedad medible.
    ?Signos radiológicos o clínicos de recurrencia o progresión de la enfermedad.
    ?Enfermedad con RE positivo, definida como células tumorales positivas para RE con ? 1 % de las células tumorales positivas para RE en el IHQ o con una puntuación IHQ (Allred) de ?3
    ?Enfermedad negativa para HER2, con una intensidad de 0, 1+ o 2+ en el IHQ y sin signos de amplificación en la ISH.
    ?Se tendrá que disponer de una muestra tumoral fijada con formalina e incluida en parafina del cáncer primario y/o recurrente para su análisis en un laboratorio central.
    ?Mujeres posmenopáusicas que cumplan todos los criterios siguientes:
    ?Edad ? 50 años y 1 año o más de amenorrea
    ?Edad < 50 años y 1 año o más de de amenorrea, con un valor de estradiol <20 pg/ml,
    ?Edad < 50 con histerectomía previa, pero ovarios intactos con un valor de estradiol < 20 pg/ml.
    ?Estado después de una ovariectomía bilateral (? 28 días antes del primer tratamiento del estudio).
    Nota: No se permite la radiación de los ovarios ni tratamiento con un agonista de la hormona liberadora de hormona luteinizante (LRHR) (acetato de goserelina o acetato de leuprolida) para la inducción de la supresión ovárica.
    ?La resistencia de la enfermedad a inhibidores de la aromatasa (IA) se define como:
    ?recidiva de la enfermedad durante, o en los 12 meses siguientes al final del tratamiento adyuvante con letrozol, anastrozol, o exemestano, o
    ?progresión de la enfermedad durante o en el mes siguiente al final del tratamiento con letrozol, anastrozol o exemastano para el cáncer de mama localmente avanzado o metastásico
    Nota: Se permite cualquier número de líneas de tratamiento hormonal antes o después del tratamiento con un IA.
    Nota: El letrozol, el anastrozol o el exemestano no tienen que ser el último tratamiento administrado antes de la aleatorización.
    ?Índices hematológicos y bioquímicos dentro de los intervalos que se indican más abajo. Estas determinaciones se deben realizar en la semana previa a la aleatorización.
    ?RAN ? 1.500 células/µl y recuento de plaquetas ? 100.000/µl
    ?Creatinina sérica <1,5 x LSN, junto con un aclaramiento de creatinina ? 50 ml/min, confirmación de que el aclaramiento de creatinina es necesario únicamente cuando la creatinina sea > 1,5 x LSN.
    ?Valor de la bilirrubina < 1,5 x LSN en ausencia de metástasis demostrables en el hígado o < 3 x LSN en presencia de metástasis hepáticas.
    ?AST o ALT ? 2,5 x LSN
    ?Cociente internacional normalizado < 1,5 y tiempo de tromboplastina parcial activado < 1,5 veces el LSN; en las pacientes que precisen tratamiento anticoagulante con fines terapéuticos, se requiere un CIN estable ? 2,5 x LSN para mitigar una posible hemorragia.
    ?Ninguna alteración clínicamente relevante y resistente al tratamiento en los valores de potasio, sodio, calcio (corregido para tener en cuenta la albúmina plasmática) o magnesio.
    ?Colesterol sérico en ayunas ? 300 mg/dl o 7,75 mmol/l y triglicéridos en ayunas ? 2,5 x LSN. Si se excedan estos umbrales, la paciente no podrá ser incluida en el estudio hasta que haya iniciado un tratamiento con estatinas y cuando se hayan alcanzado los valores antes indicados.
    ?Estado funcional del ECOG de 0-2.
    ?Mujeres sin capacidad reproductiva, incluidas las que hayan sido sometidos a histerectomía, ovariectomía bilateral, ligadura de trompas bilateral o hayan pasado la menopausia (cesación total de la menstruación durante un año o más); si la paciente tiene capacidad reproductiva, tendrá que obtener un resultado negativo en la prueba de embarazo en sangre realizada en las 2 semanas anteriores a la primera dosis del tratamiento del estudio, preferiblemente lo más cerca posible de la primera dosis, y comprometerse a utilizar anticonceptivos adecuados desde 2 semanas antes de recibir la primera dosis del producto en investigación y hasta 28 días después de recibir la última dosis del producto en investigación.
    E.4Principal exclusion criteria
    1.Presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement, any degree of brain or leptomeningeal involvement (past/present) or symptomatic pulmonary lymphangitic spread. Patients with discrete pulmonary parenchymal metastases are eligible (if respiratory function not compromised).
    2.>1 line of prior chemotherapy for MBC.
    3.Prior chemotherapy, biological therapy, androgens, thalidomide, immunotherapy, other anticancer agents or any IMPs within 14days prior to receiving study drug (not inc. palliative radiotherapy at focal sites), radiotherapy with a wide field of radiation (greater than or equal to 30% marrow or whole pelvis or spine) within 4weeks of starting study drugs, or strontium-90 (or other radiopharmaceuticals) within the past 3months or major surgery within 4weeks prior to entry into the study (excluding the placement of vascular access). With the exception of alopecia, all unresolved toxicities from prior treatment should be ?grade 1 CTCAE at start of treatment.
    4.Prior treatment with fulvestrant or everolimus.
    5.Prior treatment with PI3K inhibitors, Akt inhibitors or mTOR inhibitors.
    6.Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids (?10mg prednisolone or an equivalent dose of other antiinflammatory 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. intraarticular) are allowed. Patients on stable low dose of corticosteroids for at least 2weeks prior to randomisation are allowed.
    7.Current refractory nausea/vomiting, chronic gastrointestinal disease, inability to swallow the formulated product or previous significant bowel resection that precludes adequate absorption of the study drugs.
    8.Clinically significant pulmonary dysfunction.
    9.Significant cardiovascular disease? patients who have experienced any of the following procedures or conditions currently or in the preceding 12months:
    a.Myocardial infarction, acute coronary syndromes (inc. unstable angina), or coronary angioplasty/stenting/bypass grafting.
    b.Symptomatic congestive heart failure (CHF) New York Heart Association Classes IIIV or LVEF <50% by either ECHO or MUGA.
    c.Severe cardiac arrhythmia requiring medication or severe conduction abnormalities.
    d.Poorly controlled hypertension (resting diastolic blood pressure >100 mmHg).
    e.Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy.
    10.QTc prolongation defined as a QTc interval >470 msecs or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate <50 beats/min).
    11.Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40years of age).
    12.Clinically significant abnormalities of glucose metabolism as defined by any of the following
    a.Diagnosis of diabetes mellitus type I (irrespective of management) or uncontrolled diabetes mellitus type II.
    b.Glycosylated haemoglobin (HbA1C) ?8.0% at screening (64mmol/mol) (conversion equation for HbA1C [IFCCHbA1C (mmol/mol) = [DCCTHbA1C (%) ? 2.15] x 10.929)
    13.Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within 2weeks prior to receiving study drug (3weeks for St John?s Wort and 5weeks for phenobarbitone).
    14.Exposure to potent or moderate inhibitors or inducers of CYP2C8 within 1week prior to receiving study drug.
    15.Application of haemopoietic growth factors within 2weeks prior to receiving study drug.
    16.Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator?s opinion, gives reasonable suspicion of a disease/condition that contraindicates the use of an IMP, may affect the interpretation of the results, renders the patient at high risk from treatment complications or interferes with obtaining informed consent.
    17.History of hypersensitivity to any excipients of AZD2014, everolimus or drugs with a similar chemical structure or class to AZD2014 or everolimus.
    18.History of hypersensitivity to any excipients of fulvestrant and/or castor oil.
    19. Patients presenting with anaemia symptoms (normal haemoglobin ?90g/L).
    20.Currently receiving (and unwilling to discontinue) oestrogen replacement therapy (last dose ?7 days prior to randomisation).
    20.Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
    21.Detained persons or prisoners
    23. Pregnant or nursing women (inc. no breast feeding from 2weeks prior to receiving study drug untill 8 weeks after the last dose of IMP
    ?Enfermedad visceral metastásica potencialmente mortal, definida como afectación hepática extensa, afectación encefálica o leptomeníngea o diseminación pulmonar linfangítica sintomática. Podrán participar las pacientes con metástasis parenquimatosas pulmonares diferenciadas siempre que su función respiratoria no se encuentre significativamente afectada como consecuencia de la enfermedad
    ?No más de una línea de quimioterapia previa para el cáncer de mama metastásico.
    ?Quimioterapia previa, terapia biológica, andrógenos, talidomida, inmunoterapia, otros antineoplásicos o fármaco en investigación administrado en los 14 días previos al inicio del tratamiento, radioterapia con un amplio campo de radiación en las 4 semanas previas al inicio del tratamiento, o estroncio-9 en los últimos 3 meses o cirugía mayor en las 4 semanas previas a la inclusión (excluida la implantación de un acceso vascular), a excepción de la alopecia, todas las reacciones adversas no resueltas de un tratamiento previo no deberán ser > grado 1 de los CTACE en el momento de iniciar el tratamiento del estudio.
    ?Tratamiento previo con fulvestrant o everolimus.
    ?Tratamiento previo con inhibidores de PI3K, inhibidores de AKT u otros inhibidores de mTOR.
    ?Pacientes con inmunodepresores concomitantes o corticosteroides sistémicos crónicos durante ? 28 días a la inclusión excepto en las aplicaciones tópicas, uso de nebulizadores inhalados, colirios o inyecciones locales. Se permite una dosis baja estable de corticosteroides desde por lo menos dos semanas antes de la aleatorización.
    ?Náuseas y vómitos persistentes que no respondan a tratamiento, enfermedad gastrointestinal crónica o incapacidad para ingerir la formulación del producto o resección intestinal importante previa que impida una absorción adecuada de la medicación del estudio.
    ?Disfunción pulmonar clínicamente significativa
    ?Enfermedad cardiovascular significativa; se excluirá a las pacientes que presenten o hayan experimentado alguno de los procesos o enfermedades siguientes en los 12 meses anteriores:
    ?Antecedentes de infarto de miocardio, síndromes coronarios agudos (incluida angina inestable) o antecedentes de angioplastia coronaria/colocación de una endoprótesis/injerto de derivación.
    ?Antecedentes de ICC sintomática clases II-IV de la NYHA o FEVI < 50 % determinada mediante ECHO o MUGA.
    ?Arritmia cardiaca o anomalías graves de la conducción.
    ?Hipertensión mal controlada.
    ?Enfermedad valvular, cardiomegalia, hipertrofia ventricular o miocardiopatía.
    ?Prolongación de QTc definida como QTc >470 ms u otras alteraciones significativas del ECG, incluido bloqueo AV de segundo grado o de tercer grado o bradicardia (frecuencia ventricular < 50 latidos/min).
    ?Medicamentos concomitantes que prolongan el intervalo QT, o con factores que aumentan el riesgo de prolongación de QTc o riesgo de episodios de arritmia.
    ?Anomalías clínicas del metabolismo de la glucosa, definidas como sigue:
    ?Diagnóstico de diabetes mellitus de tipo I o mellitus de tipo II no controlada.
    ?HbA1C ? 8,0 % en la selección (64 mmol/mol)
    ?Exposición a inhibidores o inductores potentes o moderados de CYP3A4/5.
    ?Inhibidores: ketoconazol, itraconazol, indinavir, saquinovir, nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomicina, telitromicina, fluconazol, nefazodona, cimetidina, aprepitant, miconazol, fluvoxamina, glucoproteína P, zumo de pomelo, o naranjas amargas; amiodarona, eritromicina, claritromicina, verapamilo, ritonavir, diltiazem
    ?Inductores: fenitoína, rifampicina, hipérico, carbamazepina, dexametasona, primidona, griseofulvina, barbitúricos, troglitazona, pioglitazona, oxcarbazepina, nevirapina, efavirenz, rifabutina y fenobarbitona.
    Exposición a inhibidores o inductores potentes o moderados de CYP2C8 en la semana anterior a la primera dosis del tratamiento del estudio (Gemfibrozilo, trimetoprima, glitazonas, montelukast, quercetina)
    ?Aplicación de factores de crecimiento hematopoyéticos en las 2 semanas previas al administración del fármaco del estudio.
    ?Cualquier otra dato que suscite sospechas razonables de una enfermedad o proceso que contraindique el uso de un fármaco en investigación o que pueda afectar a la interpretación de los resultados, suponer un riesgo elevado de complicaciones del tratamiento para la paciente o interferir con la obtención del consentimiento informado.
    ?Hipersensibilidad al principio activo o a los excipientes o a fármacos con una estructura o clase química similar a la de AZD2014 o everolimus
    ?Antecedentes de hipersensibilidad al principio activo o a los excipientes inactivos de fulvestrant y/o al aceite de ricino
    ?Uso actual de terapia de sustitución de estrógenos (última dosis ? 7 días antes de la aleatorización)
    ?Condicionantes psicológicos, familiares, sociológicos o geográficos que no permitan cumplir el protocolo del estudio.
    ?Personas detenidas o encarceladas.
    ?Mujeres embarazadas o lactante.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure for this study is progression free survival.
    El criterio de valoración principal es la supervivencia sin progresión
    E.5.1.1Timepoint(s) of evaluation of this end point
    Progression free survival is defined as the time from the date of randomisation to the date of first documented tumour progression based on investigator assessment (using RECIST 1.1) or death from any cause, whichever occurs first.

    Tumour assessments of progression will be performed at screening, weeks 8, 16 and 24, and every 12 weeks thereafter, at the end of treatment and at followup.
    La supervivencia sin progresión se definió como el tiempo desde la fecha de la asignación al azar hasta la fecha de la primera progresión tumoral documentado sobre la base de la evaluación del investigador (mediante RECIST 1.1) o muerte por cualquier causa, lo que ocurra primero.

    Las evaluaciones tumorales de progresión se realizarán en la selección, semana 8, 16 y 24, y cada 12 semanas a partir de entonces, al final del tratamiento y en el seguimiento.
    E.5.2Secondary end point(s)
    The secondary outcome measures for this study are as follows:

    Efficacy
    1. Progression free survival, defined as the time from the date of randomisation to the date of first documented tumour progression as assessed by an independent review facility [IRF] (using RECIST 1.1) or death from any cause, whichever occurs first.
    2. Objective response, defined as a complete or partial response, based on investigator and IRF assessment using RECIST 1.1.
    3. Average change (%) in tumour size at 16 weeks compared to baseline, based on investigator and IRF assessment using RECIST 1.1? tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions.
    4. Clinical Benefit, defined as number of patients with complete or partial response or stable disease maintained ?24 weeks, based on investigator and IRF assessment using RECIST 1.1).
    5. Overall survival, defined as the time from date of randomisation to the date of death due to any cause.
    6. Duration of response, defined as the time from first documentation of complete or partial response to disease progression based on investigator and IRF assessment using RECIST 1.1.
    7. Duration of clinical benefit, defined as the time from randomisation to disease progression based on investigator and IRF assessment using RECIST 1.1 in patients with CB.
    8. Percentage change in serum of serum beta Cterminal crosslinking telopeptide of Type I collagen (?CTx) and Nterminal propeptide of Type I procollagen (PINP) from screening/baseline to each time that samples are collected.
    9. Patient reported outcomes, as assessed by the Functional Assessment of Cancer Therapy General (FACTG) scale together with the BreastAntiA and Endocrine Symptom (FACTB and AntiAES) subscales.

    Safety Outcome Measures
    The safety outcome measures for this study are as follows:
    ? Incidence of serious adverse events.
    ? Incidence of grade 3 and 4 adverse events (CTCAE, version 4.03).
    ? Incidence of all adverse events of all grades.
    ? Incidence of the following selected adverse events (any grade)
    o Hyperglycaemia
    o Diarrhoea
    o Stomatitis
    o Rash
    o Interstitial pneumonitis
    ? Adverse events leading to discontinuation of the study medication.
    ? Changes in vital signs and clinical laboratory results during and following study drug administration.

    Pharmacokinetics Outcome Measures
    The PK outcome measures for this study are as follows:
    ? Plasma drug clearance (CL/F), estimated maximum drug concentration (Cmax), elimination halflife (t1/2) and volume of distribution (Vss/F) for AZD2014.
    ? Cssmin for fulvestrant.

    Exploratory Outcome Measures
    ? Alterations in DNA and RNA, including mutational status, RNA expression levels, DNA copy number, and protein expression.
    Criterios de valoración secundarios de la eficacia son los siguientes:
    -Supervivencia sin progresión, definida como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de la primera progresión del tumor documentada basada en la evaluación realizada por un centro de revisión independiente [CRI] (utilizando los criterios RECIST 1.1) o de muerte por cualquier causa, lo que suceda antes.
    -Respuesta objetiva, definida como una respuesta completa o parcial, basada en la valoración del investigador y el CRI (utilizando los criterios RECIST 1.1).
    -Variación media (%) del tamaño del tumor a las 16 semanas en comparación con el momento basal, basada en la valoración del investigador y el CRI utilizando los criterios RECIST 1.1; el tamaño del tumor se define como la suma de los diámetros más largos de las lesiones diana (es decir, tumor medible)
    -Beneficio clínico (BC) definido como el número de pacientes con respuesta completa o parcial o enfermedad estable mantenida durante ? 24 semanas, basado en la valoración del investigador y el CRI utilizando los criterios RECIST 1.1.
    -Supervivencia global, definida como el tiempo transcurrido entre la fecha de aleatorización y la fecha de muerte por cualquier causa.
    -Duración de la respuesta, definida como el tiempo transcurrido entre la primera documentación de respuesta completa o parcial hasta la progresión de la enfermedad, basada en la valoración del investigador y el CRI utilizando los criterios RECIST 1.1
    -Duración del BC, definido como el tiempo transcurrido desde la aleatorización hasta la progresión de la enfermedad, basado en la valoración del investigador y el CRI utilizando los criterios RECIST 1.1 en pacientes con BC.
    -Variación porcentual en suero del telopéptido entrecruzado carboxiterminal del colágeno tipo I (?CTx) y el propéptido aminoterminal del procolágeno tipo I (PINP) desde el screening/momento basal hasta cada momento de recogida de muestras.
    -Valoración Funcional del Tratamiento del Cáncer - General (FACT-G) junto con las subescalas FACT-Anti-A y FACT-ES.
    -Evaluación de los parámetros farmacocineticos (FC) del AZD2014 cuando se administra conjuntamente con fulvestrant a pacientes con cáncer de mama
    -Evaluación de los parámetros FC de fulvestrant cuando se administra en monoterapia y en combinación con AZD2014 o everolimus a pacientes con cáncer de mama".
    Criterios de valoración de la seguridad són los siguientes:
    -Incidencia de acontecimientos adversos graves
    -Incidencia de acontecimientos adversos de grado 3 y 4 (CTCAE, versión 4.03)
    -Incidencia de todos los acontecimientos adversos de cualquier grado.
    -Incidencia de los siguientes acontecimientos adversos (de cualquier grado):
    ? Hiperglucemia
    ? Diarrea
    ? Estomatitis
    ? Exantema
    ? Neumonitis intersticial
    ? Astenia
    ? Cambios en la onda T
    -Acontecimientos adversos que obliguen la retirada de la medicación del estudio
    -Cambios de las constantes vitales y los resultados de los laboratorios clínicos durante y después de la administración del fármaco del estudio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy
    1. Assessed at the end of the study by an independent review facility (IRF).
    2. Assessed at the end of patient treatment (Investigator) and at the end of the study (IRF).
    3. Assessed at week 16 and at the end of the trial.
    4. Assessed at ?24 weeks (investigator) and at the end of the study (IRF).
    5. Assessed on patient death.
    6&7. Assessed at disease progression (investigator) and at the end of the study (IRF).
    8. Assessed at when the last patient has given their last sample for analysis.
    9. Assessed when the last patient has submitted their last FACT questionnaire.

    Safety
    Assessed at all study visits and analysed at the end of the study.

    Pharmacokinetics
    Analysed when final patient submits last sample.

    Exploratory
    When final patients submits last sample.
    Eficacia evaluada:
    1. al final del estudio por un centro de revisión independiente (CRI).
    2. al final del tratamiento (Investigador) y al final del estudio (CRI).
    3. en la semana 16 y al final del ensayo.
    4. en ? 24 semanas (investigador) y al final del estudio (CRI).
    5. a la muerte del paciente.
    6 y 7. a la progresión de la enfermedad (investigador) y al final del estudio (CRI).
    8. cuando el último paciente ha dado su última muestra
    9. cuando el último paciente presenta su último cuestionario FACT.

    Seguridad
    Evaluada en todas las visitas y analizada al final del estudio.

    Farmacocinética
    Analizada cuando el último paciente presenta la última muestra.

    Exploratorio
    Cuando los pacientes finales someten las últimas muestras.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group 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 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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    For the purposes of Clinical Trial Authorisation (CTA) under the European Union Directive 2001/20/EC, the study is deemed to have ended 30 days after the last patient receives the last dose of the investigational medicinal product (IMP). For all other purposes, the study end date is deemed to be the date of last data capture.
    A los efectos de la autorización del ensayo clínico (AEC) prevista en la Directiva 2001/20/CE de la Unión Europea, el estudio se considerará finalizado 30 días después de que la última paciente reciba la última dosis del medicamento en investigación (MEI). A todos los demás efectos, se considerará como fecha de finalización del estudio la fecha de la última recogida de datos.
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 240
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 240
    F.4.2.2In the whole clinical trial 240
    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)
    Patients will be treated until PD, treatment limiting toxicity, death, elective withdrawal, study completion/termination.
    At PD, patients on the fulvestrant+everolimus arm may be able to cross over to the fulvestrant+AZD2014 arm.
    The Sponsor does not intend to continue providing study drug/any other study treatment to participants if they withdraw from the study or when it closes.
    When the patient finished treatment, study doctors will discuss their treatment options to ensure ongoing care.
    El tratamiento continuará hasta la progresión de la enfermedad, excepto si hay signos de toxicidad inaceptable o si la paciente solicita su retirada.
    A la PE, los pacientes del grupo everolimus+ fulvestrant podrán pasar al brazo fulvestrant + AZD2014.
    El sponsor no proporcionará el fármaco o cualquier otro tratamiento del estudio a los participantes si se retiran o cuando se cierre.
    A terminar el tratamiento, los médicos discutirán las opciones para garantizar una atención continua.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-01-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-10
    P. End of Trial
    P.End of Trial StatusOngoing
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