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    Summary
    EudraCT Number:2011-005194-23
    Sponsor's Protocol Code Number:D0102C00006
    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:2012-07-26
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2011-005194-23
    A.3Full title of the trial
    A Phase IIa Multi-centre Randomised Double-Blind Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of AZD8931 in Combination with Paclitaxel versus Paclitaxel alone in Patients with Metastatic, Gastric or Gastro-oesophageal Junction, Cancer who progress following First Line Therapy and are Ineligible for Treatment with trastuzumab by HER2 Status (SAGE)
    Estudio fase IIa multicéntrico, doble ciego, controlado con placebo para evaluar la eficacia, seguridad y farmacocinética de AZD8931 en combinación con paclitaxel versus paclitaxel solo, en pacientes con cáncer gástrico o de la unión gastroesofágica metastásico, que progresa tras una primera línea de tratamiento y no son elegibles para tratamiento con trastuzumab (SAGE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase IIa Multi-centre Randomised Double-Blind Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of AZD8931 in Combination with Paclitaxel versus Paclitaxel alone in Patients with Metastatic, Gastric or Gastro-oesophageal Junction, Cancer who progress following First Line Therapy and are Ineligible for Treatment with trastuzumab by HER2 Status (SAGE)
    A.3.2Name or abbreviated title of the trial where available
    SAGE
    SAGE
    A.4.1Sponsor's protocol code numberD0102C00006
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca AB
    B.5.2Functional name of contact pointInformation Centre
    B.5.3 Address:
    B.5.3.1Street AddressN/A
    B.5.3.2Town/ cityN/A
    B.5.3.3Post codeN/A
    B.5.3.4CountrySweden
    B.5.6E-mailinformation.centre@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameAZD8931 film-coated tablet 20mg
    D.3.2Product code AZD8931
    D.3.4Pharmaceutical form Film-coated 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 INNnot available
    D.3.9.1CAS number 1196531-39-1
    D.3.9.2Current sponsor codeAZD8931difumarate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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 nameAZD8931 film-coated tablet 40mg
    D.3.2Product code AZD8931
    D.3.4Pharmaceutical form Film-coated 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 INNnot available
    D.3.9.1CAS number 1196531-39-1
    D.3.9.2Current sponsor codeAZD8931difumarate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic, Gastric or Gastro-oesophageal Junction Cancer
    Cancer Gastrico o de la unión gastroesofágica metastásico
    E.1.1.1Medical condition in easily understood language
    Metastatic, Gastric or Gastro-oesophageal Junction, Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10071114
    E.1.2Term Metastatic gastric adenocarcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the relative efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by comparison of the change in tumour size at 8 weeks
    Evaluar la eficacia relativa de AZD8931 más paclitaxel en comparación con paclitaxel solo mediante una comparación de la variación del tamaño del tumor a las 8 semanas
    E.2.2Secondary objectives of the trial
    · To assess the relative efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of progression-free survival (PFS)
    · To investigate the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of objective response rate (ORR)
    · To assess the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of the percentage of patients without progressive disease (i.e. patients with CR, PR or SD) at 8 weeks
    · To assess the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of overall survival (OS)
    · To compare and assess the safety and tolerability of AZD8931 plus paclitaxel compared with paclitaxel alone
    · To investigate the pharmacokinetics (PK) of AZD8931 and AZD8931 O-desmethyl metabolite in a metastatic, gastric or gastro-oesophageal junction, cancer patient population.
    Evaluar la eficacia relativa de AZD8931 más paclitaxel en comparación con paclitaxel solo mediante una evaluación de la supervivencia sin progresión (SSP).
    Investigar la eficacia de AZD8931 más paclitaxel en comparación con paclitaxel solo mediante una evaluación de la tasa de respuestas objetivas (TRO).
    Evaluar la eficacia de AZD8931 más paclitaxel en comparación con paclitaxel solo mediante una evaluación del porcentaje de pacientes sin progresión de la enfermedad (es decir, pacientes con RC, RP o EE) a las 8 semanas.
    Evaluar la eficacia de AZD8931 más paclitaxel en comparación con paclitaxel solo mediante una evaluación de la supervivencia global (SG).
    Comparar y evaluar la seguridad y tolerabilidad de AZD8931 más paclitaxel en comparación con paclitaxel solo.
    Investigar la FC de AZD8931 y el metabolito O-desmetílico de AZD8931 en una población de pacientes con cáncer gástrico o de la unión gastroesofágica metastásico
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of signed, written informed consent prior to any study specific procedures
    2. Male or female aged 18 years or older (20 years or older in Japan)
    3. Histological diagnosis of gastric adenocarcinoma (including adenocarcinoma of the gastro-oesophageal junction)
    4. Patients must have radiologically confirmed progression following 1st line fluoropyrimidine and platinum based treatment for metastatic gastric cancer (the date of progression and start of first line treatment to be captured on the database)
    5. Suitable for paclitaxel therapy
    6. At least one lesion, not previously irradiated and not chosen for a mandatory fresh tumour biopsy during the study screening period, that can be accurately measured at baseline as ?10mm in longest diameter (except lymph nodes which must have short axis ?15mm) by computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeat assessment i.e. the tumour site chosen for mandatory biopsy will not be deemed measurable and will be classed as a non-target lesion at baseline RECIST 1.1 assessment.
    7. World Health Organisation (WHO) performance status 0-1, minimum life expectancy of 12 weeks from proposed first dose date, no deterioration within 2 weeks of screening and first dose. Investigator has discretion to exclude rapidly progressive gastric cancer (such as those patients with rapid deterioration of performance status, requiring repeated drainage of ascites, patients with low or rapidly decreasing albumin or patients requiring feeding assistance with devices such as PEG)
    8. Ineligible for trastuzumab treatment by local assessment. This should include IHC analysis to determine HER2 status with further testing by FISH/CISH for IHC 2+ patients. Eligible patients are those defined as; HER2 IHC 0, HER2 IHC 1+, or HER2 IHC 2+ (FISH ?ve)
    9. Collection of the original archival diagnostic (or more recent archival) tumour sample for retrospective central HER2 assessment, followed by exploratory retrospective biomarker analysis. Both primary lesion and metastatic sites are acceptable.
    10. Women should be using adequate contraceptive measures (see Appendix J), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child bearing potential, or must have evidence of non-child bearing potential by fulfilling one of the following criteria at screening:
    · Post menopausal defined as:
    - Aged ? 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
    - Aged <50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and with luteinising hormone and follicular stimulating hormone levels in the post menopausal range
    · Documentation of irreversible surgical sterilization by hysterectomy, and/or bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal ligation
    For inclusion in the optional PGx sample collection:
    11. Provision of informed consent for PGx sample collection
    For inclusion in the optional fresh tumour biopsy upon RECIST 1.1 defined progression:
    12. Provision of informed consent for tumour sample collection
    If a patient declines to participate in the optional components of the study (PGx or additional tumor sample collection) there will be no penalty or loss of benefit to the patients. The patient will not be excluded from other aspects of the study to which they have consented.
    13. Patients must provide fresh baseline (pre-treatment) excisional or core needle tumour biopsies from a suitable and accessible site (other than from a key target lesion site chosen for the primary efficacy assessment [see inclusion criteria 6]).
    1. Dar su consentimiento informado por escrito y firmado antes de realizar cualquier procedimiento específico del estudio.
    2. Varón o mujer con una edad mínima de 18 años (20 años en Japón).
    3. Diagnóstico histológico de adenocarcinoma gástrico (incluido adenocarcinoma de la unión gastroesofágica).
    4. Progresión confirmada radiológicamente después de un tratamiento de primera línea basado en fluoropirimidina y platino por cáncer gástrico metastásico (la fecha de progresión y el inicio del tratamiento de primera línea han de introducirse en la base de datos).
    5. Apto para recibir tratamiento con paclitaxel.
    6. Al menos una lesión, no irradiada previamente y no seleccionada para practicar la biopsia tumoral reciente obligatoria durante el período de selección del estudio, que pueda medirse con exactitud en el momento basal como ? 10 mm de diámetro mayor (excepto los ganglios linfáticos, que deben tener un eje menor ? 15 mm) mediante tomografía computarizada (TC) o resonancia magnética (RM) y que sea adecuada para realizar evaluaciones repetidas exactas, es decir, el foco tumoral elegido para la biopsia obligatoria no se considerará medible y se clasificará como lesión no diana en la evaluación basal conforme a los criterios RECIST 1.1.
    7. Estado funcional de la Organización Mundial de la Salud (OMS) de 0-1, esperanza de vida mínima de 12 semanas desde la fecha prevista de administración de la primera dosis, ausencia de deterioro en las 2 semanas previas a la selección y la primera dosis. El investigador tendrá potestad para descartar un cáncer gástrico rápidamente progresivo (por ejemplo, pacientes con deterioro rápido del estado funcional y necesidad de drenaje repetido de ascitis, pacientes con albúmina baja o en rápida disminución o pacientes con necesidad de asistencia para la alimentación con dispositivos como sonda de gastrostomia percutanea (PEG).
    8. No elegible para tratamiento con trastuzumab según la evaluación local. Ha de incluir un análisis de IHQ para determinar el estado de HER2, con análisis adicionales mediante FISH/CISH en los pacientes con IHQ de 2+. Los pacientes elegibles se definen como IHQ de HER2 de 0, 1+ o 2+ (FISH -).
    9. Obtención de la muestra tumoral diagnóstica de archivo original (o de archivo más reciente) para una evaluación centralizada retrospectiva de HER2, seguida de un análisis retrospectivo exploratorio de biomarcadores. Tanto la lesión primaria como los focos metastásicos serán aceptables.
    10. Las mujeres tendrán que utilizar métodos anticonceptivos adecuados (véase el apéndice J), no podrán estar dando el pecho y deberán dar negativo en una prueba de embarazo realizada antes del inicio de la administración en caso de estar en edad fértil, o bien tener constancia de no estar en edad fértil mediante el cumplimiento de uno de los criterios siguientes en la selección:
    ? Ser posmenopáusica, definido como:
    Edad ? 50 años y amenorrea durante al menos 12 meses tras el cese de todos los tratamientos hormonales exógenos.
    Edad < 50 años y amenorrea durante al menos 12 meses tras el cese de todos los tratamientos hormonales exógenos y concentraciones de lutropina y folitropina en el intervalo posmenopáusico.
    ? Documentación de una esterilización quirúrgica irreversible mediante histerectomía, ovariectomía bilateral o salpingectomía bilateral, con exclusión de una ligadura de trompas bilateral.
    Para poder participar en la obtención opcional de muestras para FG:
    11. Otorgamiento del consentimiento informado para obtener la muestra de sangre para FG.
    Para poder participar en la obtención opcional de una biopsia tumoral reciente en el momento de progresión definida según los criterios RECIST 1.1:
    12. Otorgamiento del consentimiento informado para obtener muestras tumorales.
    Si un paciente rechaza participar en los componentes opcionales del estudio (FG u obtención de muestras tumorales adicionales), no incurrirá en ninguna penalización ni pérdida de beneficios a los que tenga derecho. No se le excluirá de otras partes del estudio para las que hayan otorgado su consentimiento.
    13. Los pacientes deberán someterse a biopsias tumorales por escisión o con aguja gruesa basales (antes del tratamiento) recientes a partir de un lugar apropiado y accesible (distinto de un foco de lesión diana clave elegido para la evaluación principal de la eficacia [véase el criterio de inclusión 6])
    E.4Principal exclusion criteria
    1.Have received more than 1 prior chemotherapy regimen for metastatic gastric cancer. (chemotherapy as adjuvant treatment is permitted).
    2.Any prior taxane therapy (at any time from diagnosis of gastric cancer)
    3.Any prior therapy with an inhibitor of ErbB1 or ErbB2 (eg, lapatinib)
    4.Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count <1.5 x 109/L or platelet count <100 x 109/L
    5.Moderate or severe renal impairment.
    6.Haemoglobin ?9 g/dL (5.59 mmol/L), any blood transfusion must be >14 days prior to the determination of the haemoglobin levels
    7.Inadequate liver function defined in protocol;
    8.Resting ECG with measurable QTc(F) interval of >480 msec at 2 or more time points within a 24 hour period
    9.Cardiac ejection fraction outside institutional range of normal or ?50% (whichever is higher) as measured by echocardiogram
    10.Known uncontrolled or symptomatic angina, arrhythmias or congestive heart failure, evidence of transmural infarction on ECG, poorly controlled hypertension (systolic >180 mmHg or diastolic >100 mmHg), significant valvular disease or history of high risk dysrrhythmia (such as ventricular fibrillation or ventricular tachycardia [includes ventricular triplets])
    11.Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
    12.Active or uncontrolled systemic disease which in the investigator?s / delegate?s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol
    13.History or repeated unexplained episodes of syncope/dizziness
    14.Medical diagnosis of acne rosacea, psoriasis, severe atopic eczema
    15.Concurrent second primary malignancy (except in situ carcinoma of the cervix). Patients with a prior cancer are eligible if they are disease-free with no evidence of recurrence or relapse in the past 5 years
    16.Unresolved toxicity >CTCAE grade 2 (except alopecia) from previous anti-cancer therapy
    17.Unable to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation.
    18.Unable to discontinue any medication or herbal supplement with known moderate or potent inhibitory effect on CYP3A4, or potent inducing effects on CYP3A4. Such drugs must have been discontinued for an appropriate period prior to starting AZD8931. Guidance on medicines to avoid and on washout periods is given in Appendix G to this protocol
    19.Known hypersensitivity to AZD8931
    20.Involvement in the planning and/or conduct of the study
    21.Receipt of investigational drug within 30 days or five half lives, whichever is longer, of the first dose of IP
    22.Prior diagnosis of dry eye syndrome, eyelid or eyelash abnormalities
    23.History or current evidence of any of the following:
    -Any eye injury in the previous 3 months or a prior eye injury still associated with persistent or recurrent symptoms or impairment of vision
    -Corneal surgery (laser refractive surgery performed more than 3 months prior to the start of the study is allowed and should be recorded in surgical history)
    -Orbital irradiation
    -Collagen vascular, chronic inflammatory or degenerative disease with eye involvement (eg, rheumatoid, Sjögren?s syndrome, systemic lupus erythematosus )
    -Clinically significant ocular surface disease ie, diseases of the conjunctiva and cornea (including atopic keratoconjunctivitis, Stevens-Johnson syndrome, ocular cicatricial pemphigoid or chemical burns, herpes simplex or herpes zoster virus eye disease)
    24.History of maculopathy in patients with impaired visual acuity. (Impaired visual acuity is defined as best corrected near visual acuity <0.4 or best corrected distance visual acuity (including with pinhole) <0.7) Note: patients with cataracts are allowed. No eye symptoms must be present on Day 1 of AZD8931 dosing
    25.Last dose of prior anticancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, targeted therapy, biologic therapy, or tumour embolisation) received within 14 days (within 6 weeks for nitrosurea or mitomycin C) prior to the first dose of treatment with investigational product (IP) (AZD8931 or placebo). If sufficient wash-out time has not occurred due to schedule or PK properties, a longer wash-out period will be required, as agreed by AZ and the investigator / delegate
    For optional PGx component only:
    26.Previous allogenic bone marrow transplant
    27.Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.
    1. Haber recibido más de un régimen previo de quimioterapia por cáncer gástrico metastásico. (Se permitirá la quimioterapia como tratamiento adyuvante).
    2. Cualquier tratamiento previo con taxanos (en cualquier momento desde el diagnóstico del cáncer gástrico).
    3. Cualquier tratamiento previo con un inhibidor de EGFR o HER2 (pe, lapatinib).
    4. Reserva medular insuficiente, según lo indicado por un recuento absoluto de neutrófilos < 1,5 x 109/l o un recuento de plaquetas < 100 x 109/l.
    5. Insuf. renal moderada o grave. Si la creatinina es > 1 vez el LSN, se calculará el aclaramiento de creatinina o la filtración glomerular con la fórmula de Cockcroft-Gault o la fórmula MDRD (Modif of Diet in Renal Disease). Aclaramiento de creatinina o filtración glomerular < 50 ml/min.
    6. Hemoglobina ? 9 g/dl (5,59 mmol/l); cualquier transfusión de sangre deberá realizarse > 14 días antes de determinar la concentración de hemoglobina.
    7. Función hepática inadecuada, definida como;
    bilirrubina sérica > 2 veces el LSN
    y ALT o AST > 2,5 veces el LSN en ausencia de metástasis hepáticas constatadas
    y FA > 2,5 veces el LSN en ausencia de metástasis hepáticas constatadas
    o FA, AST o ALT > 5,0 veces el LSN si el investigador considera que guarda relación con metástasis hepáticas. Una FA elevada no es motivo de exclusión si se debe a la presencia de metástasis óseas y, por lo demás, la función hepática se considera adecuada, según el criterio del investigador.
    8. ECG en reposo con intervalo QTc(F) medible > 480 ms en 2 o más momentos durante un período de 24 horas 9. Fracción de eyección cardíaca por fuera del intervalo normal del centro o ? 50% (lo que sea mayor) medida mediante ecocardiograma (o ventriculografía isotópica en equilibrio (MUGA) cuando no pueda realizarse un ecocardiograma o no sea concluyente).
    10. Angina de pecho, arritmias o insuficiencia cardíaca congestiva no controladas o sintomáticas, prueba de un infarto transmural en el ECG, hipertensión arterial mal controlada (sistólica > 180 mm Hg o diastólica > 100 mm Hg), valvulopatía importante o antecedentes de arritmias de alto riesgo (como fibrilación ventricular o taquicardia ventricular [incluye tripletes ventriculares]).
    11. Antecedentes personales de neumopatía intersticial, neumopatía intersticial por fármacos, neumonitis por radiación con necesidad de tratamiento con esteroides o cualquier indicio de neumopatía intersticial clínicamente activa.
    12. Enf. sistémica activa o no controlada que, en opinión del investigador o delegado, hace que no sea deseable que el paciente participe en el ensayo o que podría poner en peligro el cumplimiento del protocolo.
    13. Antecedentes o episodios inexplicables repetidos de síncope/mareo.
    14. Diagnóstico médico de acné rosácea, psoriasis o eccema atópico grave.
    15. Segunda neoplasia maligna primaria concomitante (salvo carcinoma in situ de cuello uterino). Los pacientes con un cáncer previo podrán participar si se mantienen sin enfermedad y sin datos de recurrencia o recidiva en los 5 últimos años
    16. Toxicidad no resuelta de grado > 2 de los CTCAE (exc. alopecia) por el tratamiento antineoplásico previo.
    17. Incapacidad de suspender el tratamiento con fármacos que entrañan riesgo de Torsades de Pointes debido a una prolongación del QT. En el ap. G de este CSP se orienta sobre los medicamentos a evitar y los períodos de lavado propuestos.
    18. Incapacidad de suspender cualquier medicamento o suplemento de herbolario con efectos inhibidores moderados o potentes sobre CYP3A4 o con efectos inductores potentes sobre CYP3A4. Estos medicamentos deberán haberse suspendido durante un período adecuado antes de iniciar la administración de AZD8931. En el ap. G de este protocolo se orienta sobre los medicamentos a evitar y los períodos de lavado propuestos.
    19. Hipersensibilidad conocida a AZD8931, a sus excipientes o a fármacos de su grupo (incluidos inhibidores de la tirosina cinasa V oral).
    20. Participación en la planificación o realización del estudio (se aplica a personal de AZ y del centro del estudio).
    21. Recepción del fármaco en investigación en los 30 días o en el período equivalente a cinco semividas, lo que suponga más tiempo, antes de la primera dosis del PI (AZD8931 o placebo).
    22. Diagnóstico previo de síndrome de ojo seco o de anomalías de los párpados o las pestañas.
    23. Antecedentes/indicios de las siguientes situaciones:
    Cualquier lesión ocular, Cirugía corneal, Irradiación orbitaria, Enf. del colágeno vascular, Enf. de la superficie ocular clínicamente significativa.
    24. Antecedentes de maculopatía en pacientes con deterioro de la agudeza visual.
    25. Últ. dosis del tratamiento antineoplásico previo. recibida en los 14 días anteriores a la primera dosis del tratamiento con el PI (AZD8931 o placebo). En caso de que no haya transcurrido un tiempo de lavado suficiente debido al calendario o las propiedades FC, se necesitará un tiempo de lavado más prolongado.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy- Change in tumour size at 8 weeks
    Eficacia- Variacion del tamaño del tumos a las 8 semanas.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change in tumour size at 8 weeks
    Variacion del tamaño del tumos a las 8 semanas.
    E.5.2Secondary end point(s)
    Efficacy-
    -Progression Free Survival (PFS)
    -Overall survival (OS)
    -Objective response rate (ORR)
    -Percentage of patients without progressive disease at 8 weeks (i.e. patients with CR, PR or SD)
    Safety- Adverse Events
    - Deaths
    - Laboratory findings (clinical chemistry, haematology, urinalysis)
    - Vital signs
    - Physical Examination
    - Ophthalmic assessments
    Pharmacokinetic
    - Plasma concentrations of AZD8931 and AZD8931 O-desmethyl metabolite
    - Pharmacokinetic parameters including (but not restricted to):
    AZD8931: AUCss, Css,max, Css,min,tssmax, CLss/F and tlast
    AZD8931 O-desmethyl metabolite : AUC0-t, Cmax, tmax and AUC0-t metabolite:parent ratio

    - Cardiac assessments (ECG, ECHO/MUGA)
    Eficacia
    - Supervivencia sin progresión (SSP).
    - Supervivencia global (SG).
    - Tasa de respuestas objetivas (TRO).
    - Porcentaje de pacientes sin progresión de la enfermedad a las 8 semanas (es decir, pacientes con RC, RP o EE).
    - Estado basal (antes del tratamiento) del tumor en cuanto al receptor HER2 y HER3.
    - Estado basal (antes del tratamiento) del tumor en cuanto a parejas de hetero/homodímeros de HER.
    ? Seguridad
    - Acontecimientos adversos.
    - Muertes.
    - Datos analíticos (bioquímica clínica, hematología, análisis de orina).
    - Constantes vitales.
    - Exploración física.
    - Evaluaciones oftalmológicas.
    - Evaluaciones cardíacas (ECG, ecocardiograma/MUGA).
    ? Farmacocinética
    - Concentraciones plasmáticas de AZD8931 y el metabolito O-desmetílico de AZD8931.
    - Parámetros farmacocinéticos, entre otros:
    AZD8931: AUCss, Css,máx, Css,mín, tss,máx, CLss/F y túltima.
    Metabolito O-desmetílico de AZD8931: AUC0-t, Cmáx, tmáx y AUC0-t cociente metabolito:sustancia original.

    ? Exploratorias
    - Estado basal (antes del tratamiento) del tumor en cuanto a biomarcadores clave relacionados con la via de señalización de HER.
    - Concentraciones de biomarcadores y variaciones con respecto al momento basal de los biomarcadores (por ejemplo, biomarcadores clave relacionados con la via de señalización de HER).
    - Polimorfismos del huésped (FG).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessment made during trial
    Evaluacion durante el ensayo
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    China
    Italy
    Japan
    Korea, Republic of
    Spain
    Taiwan
    United Kingdom
    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
    Patients may continue to receive AZD8931 as long as they are continuing to show clinical benefit, as judged by the investigator, and in the absence of discontinuation
    criteria
    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 months3
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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: 21
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 39
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 17
    F.4.2.2In the whole clinical trial 60
    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)
    Each patient continues treatment after completion of trial will be chosen at the discretion of the investigator, and according to local practice
    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 Decision2012-10-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-10
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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