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    Summary
    EudraCT Number:2015-004828-66
    Sponsor's Protocol Code Number:MedOPP112
    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:2016-05-18
    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 number2015-004828-66
    A.3Full title of the trial
    A phase IIa clinical trial to evaluate the safety and efficacy of osirmertinib (AZD9291) in first-line patients with EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer and concomitant EGFR T790M mutation at time of diagnosis (AZENT study)
    "Ensayo clínico de fase IIa de la seguridad y eficacia de osirmertinib (AZD9291) como tratamiento de primera línea en pacientes con cáncer de pulmón no microcítico localmente avanzado o metastásico EGFR mutado con presencia concomitante de la mutación EGFR T790M al diagnóstico (Estudio AZENT)”
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase IIa clinical trial to evaluate the safety and efficacy of osirmertinib in first-line patients withadvanced or metastatic non-small cell lung cancer (AZENT study)
    Ensayo clínico de seguridad y eficacia de osirmertinib como tratamiento de primera línea en pacientes con cáncer de pulmón no microcítico localmente avanzado o metástasico (estudio AZENT)
    A.3.2Name or abbreviated title of the trial where available
    AZENT
    AZENT
    A.4.1Sponsor's protocol code numberMedOPP112
    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 SponsorMedica Scientia Innovation Research (MedSIR ARO)
    B.1.3.4CountrySpain
    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 organisationMedica Scientia Innovation Research (MedSIR ARO)
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street AddressRambla de Cataluña, 2-4D;
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08007
    B.5.3.4CountrySpain
    B.5.4Telephone number0034932214135
    B.5.5Fax number0034932992382
    B.5.6E-mailmargarida.garcia@medsir.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TAGRISSO
    D.2.1.1.2Name of the Marketing Authorisation holderASTRAZENECA AB
    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 nameTAGRISSO
    D.3.2Product code EU/1/16/1086/001
    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 INNND
    D.3.9.1CAS number ND
    D.3.9.2Current sponsor codeAZD9291
    D.3.9.3Other descriptive nameOSIMERTINIB MESYLATE
    D.3.9.4EV Substance CodeSUB176836
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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 TAGRISSO
    D.2.1.1.2Name of the Marketing Authorisation holderASTRAZENECA AB
    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 nameTAGRISSO
    D.3.2Product code EU/1/16/1086/001
    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 INNND
    D.3.9.1CAS number ND
    D.3.9.2Current sponsor codeAZD9291
    D.3.9.3Other descriptive nameOSIMERTINIB MESYLATE
    D.3.9.4EV Substance CodeSUB176836
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients diagnosed with stage IIIB or IV non-small cell lung cancer carrying the EGFR activating mutation and confirming concomitant T790M mutation during screening who have not received prior treatment for this advanced disease will be enrolled in this study. Patients are not eligible if they are candidates for local curative treatment.
    En este estudio se incluirán pacientes diagnosticados de carcinoma no microcítico de pulmón EIIIB o IV, portadores de mutación activadora de EGFR y mutación T790M concomitante, no tratados previamente con tratamientos para la enfermedad avanzada. Los pacientes no son elegibles si son candidatos para un tratamiento local con intención curativa.
    E.1.1.1Medical condition in easily understood language
    Patients diagnosed with stage IIIB or IV non-small cell lung cancer who have not received prior treatment for this advanced disease will be enrolled in this study.
    En este estudio se incluirán pacientes diagnosticados de carcinoma no microcítico de pulmón EIIIB o IV, no tratados previamente con tratamientos para la enfermedad avanzada.
    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 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10029521
    E.1.2Term Non-small cell lung cancer stage IIIB
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    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 evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria.
    Evaluar la eficacia de AZD9291 en términos de tasa de respuesta objetiva en los pacientes con CPNM no escamoso avanzado con mutaciones de EGFR y la mutación EGFR T790M al diagnóstico, según criterios RECIST 1.1.
    E.2.2Secondary objectives of the trial
    Determine the safety and tolerability profile of osimertinib (AZD9291)
    Determine other efficacy parameters such as progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), duration of response (DOR), disease control rate (DCR), and tumor shrinkage (TS).
    Correlate the parameters of clinical response efficacy documented with the EGFR mutational status.
    Carry out a longitudinal analysis of EGFR mutations (including the T790M mutation) in plasma and serum.
    Determine levels of BIM mRNA as well as mRNA levels of other biomarkers related to EGFR TKI response and determine whether they are predictors of treatment response.
    To identify mechanisms of acquired resistance to osimertinib (AZD9291); mutations at the site of covalent binding to the drug (C797) or other mutations in tissue or blood.
    To analyze biomarkers related to mechanisms of resistance to the treatment.
    ✓ Determinar el perfil de seguridad y tolerabilidad de AZD9291
    ✓ Determinar parámetros de eficacia como la Supervivencia Libre de Progresión (SLP), la Supervivencia Global (SG), el Tiempo hasta Fracaso del Tratamiento (TFT), el Tiempo de Duración de la Respuesta (TDR), la Tasa de Control de la Enfermedad (TCE) y la Disminución del Tamaño del Tumor (DTT
    ✓ Correlacionar los parámetros de eficacia de respuesta clínica documentada con el status mutacional de EGFR
    ✓ Analizar mutaciones de EGFR (incluída la T790M) de forma longitudinal en plasma y suero
    ✓ Determinar los niveles de mRNA de BIM así como los niveles de mRNA de otros biomarcadores relacionados con la respuesta a los TKI de EGFR y evaluar si es predictor de respuesta al tratamiento
    ✓ Identificar mecanismos de resistencia adquirida a AZD9291; mutaciones en el sitio de unión covalente al fármaco (C797) u otras mutaciones en tejido o en sangre
    ✓ Analizar biomarcadores relacionados con mecanismos de resistencia al tratamiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria
    1. Patient aged 18 years or older.
    2. Patients with histological confirmation of locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M mutation who are not candidates for local curative treatment.
    3. Patients with a M1a stage according to the TNM version 7 including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease for which there is no curative treatment (including patients who progress after chemoradiotherapy in stage III disease).
    4. Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally.
    5. ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2.
    6. Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Patients with asymptomatic and stable brain metastases are eligible for the study.
    7. Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the primary tumor or metastatic tumor tissue, within the 60 days prior to study entry.
    8. Life expectancy ≥12 weeks.
    9. Adequate hematologic function: Absolute neutrophil count (ANC) > 1.5 x 109/L, platelet count > 100.0 x109/L and hemoglobin > 9.0 g/dL (> 6.2 mmol/L).
    10. Adequate coagulation: INR ≤ 1.5.
    11. Adequate liver function: Total bilirubin < 1.5 × ULN, ALT and/or AST < 2.5 × ULN, alkaline phosphatase < 5 ULN, except in the presence of single bone metastases and in absence of any liver disorders.
    12. Adequate renal function: Calculated creatinine clearance > 50 mL/min (Cockroft-Gault) and proteinuria < 2+ (dipstick).
    13. Capacity to swallow, patient capable of completing treatment and accessible, ensuring proper follow-up.
    14. Patients able to complete study and within geographical proximity allowing for adequate follow-up.
    15. Resolution of all acute toxic effects of any previous anti-cancer therapy (which can only be adjuvant or neoadjuvant) or previous surgical interventions not exceeding grade  1 according to the NCI CTCAE version 4.0 (except for alopecia or other side effects that the investigator does not consider to be a risk to patient safety).
    16. All men or women of childbearing potential must use a contraception method during the study treatment and for at least 12 months after the last dose of the study drug. Sexually active men and women of childbearing potential who are unwilling to use a contraception method are not eligible for the study.
    17. The written informed consent (IC) must be signed and dated by the patient and the investigator before any study intervention takes place.
    Criterios de inclusión
    1. Mayor de 18 años de edad.
    2. Pacientes con confirmación histológica de cáncer de pulmón no microcítico (CPNM) no escamoso metastásico o localmente avanzado no candidatos a tratamiento local con intención curativa, con mutación activadora de EGFR y mutación T790M concomitante.
    3. Pacientes con estadio M1a según TNM versión 7 incluyendo M1a (derrame maligno) o M1b (metástasis a distancia), o enfermedad localmente avanzada no tributaria de tratamiento curativo (incluyendo pacientes que progresan tras quimioradioterapia en enfermedad estadio III).
    4. Pacientes con delección o mutación en el exón 19, exón 21 (L858R, L861Q) o exón 18 (G719X) de EGFR y mutación T790M concomitante pretratamiento confirmadas centralmente.
    5. Estado funcional ECOG (Eastern Cooperative Oncology Group) inferior o igual a 2.
    6. Existencia de enfermedad medible o evaluable (según criterios RECIST 1.1). Los pacientes con metástasis cerebrales asintomáticas y estables serán elegibles para el estudio.
    7. Posibilidad de disponer de una muestra de tejido suficiente, mediante biopsia o resección quirúrgica del tumor primario o de tejido tumoral metastático, en los 60 días previos a la entrada en el estudio.
    8. Esperanza de vida superior o igual a 12 semanas.
    9. Función hematológica adecuada: recuento absoluto de neutrófilos (RAN) > 1,5 x 109/l, recuento de plaquetas > 100,0 x109/l y hemoglobina > 9,0 g/dl (> 6,2 mmol/l).
    10. Coagulación adecuada: INR≤ 1.5
    11. Función hepática adecuada: bilirrubina total < 1.5 × LAN, ALT y/o AST < 2.5 × LAN, fosfatasa alcalina < 5 LAN, excepto en la presencia de metástasis óseas únicas y en la ausencia de alteración hepatica
    12. Función renal adecuada: aclaramiento de creatinina calculado > 50 mL/min (Cockroft-Gault) y proteinuria < 2+ (dipstick).
    13. Capacidad oral de deglución, paciente capaz de cumplimiento correcto del tratamiento y accessible para un correcto seguimiento.
    14. Cumplimiento y proximidad geográfica del paciente que permita un seguimiento adecuado.
    15. Resolución de todos los efectos tóxicos agudos de cualquier tratamiento antineoplásico previo (que sólo podrá ser adyuvante o neoadyuvante) o intervenciones quirúrgicas previas hasta un grado ≤ 1 según los CTCAE del NCI, versión 4.0 (excepto alopecia u otros efectos secundarios que el investigador no considere un riesgo para la seguridad del paciente).
    16. Todos los hombres o mujeres en edad fértil deben usar un método contraceptivo durante el tratamiento de estudio y por un periodo de mínimo 12 meses después de la última administración del fármaco en estudio. No serán elegibles para el estudio hombres y mujeres sexualmente activos en edad fértil que no estén dispuestos a usar un método contraceptivo durante el estudio.
    17. El consentimiento informado escrito (CI) debe ser firmado y datado por el paciente y el investigador antes de cualquier intervención del estudio.
    E.4Principal exclusion criteria
    Any patient meeting ANY of the following criteria will be excluded from the study:
    1. Locally advanced lung cancer candidate for curative treatment through radical surgery and/or radio(chemo)therapy.
    2. Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC with predominantly squamous cell cancer, or with any small-cell lung cancer component.
    3. Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment that have not been confirmed centrally.
    4. Patients who have received prior antineoplastic treatment for advanced disease.
    5. Second active neoplasia; e.g. patients diagnosed with a potentially lethal cancer for which they may be receiving treatment (but are not obliged to do so).
    6. Patients with just one measurable or evaluable tumor lesion that has been resected or irradiated prior to their enrollment in the study.
    7. Medical history of Interstitial Lung Disease (ILD) induced by drugs, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD.
    8. Any of the following criteria:
    • Corrected QT Interval (QTc) >470 msec, obtained from 3 ECGs at rest, using the QTc value determined according to the clinical screening ECG machine.
    • Any clinically significant abnormality in ECG rhythm, conduction or morphology at rest.
    • Any factor that increases the risk of QTc prolongation or risk of irregular heartbeat or sudden inexplicable death under the age of 40 in first-degree relatives or any concomitant medications that prolong the QT interval.
    9. Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or leptomeningeal disease indicated by known clinical symptoms, cerebral edema and/or progressive neoplasia. Patients with history of CNS metastasis or compression of the spinal cord are eligible if they have received local final treatment (e.g., radiotherapy, stereotactic surgery) and if they have remained clinically stable without using anticonvulsants and corticosteroids for a minimum of 4 weeks prior to the first day of study treatment.
    10. Refractory nauseas and vomiting, chronic gastrointestinal disease, inability to swallow study drug or significant intestinal resection that restricts the adequate absorption of osimertinib (AZD9291).
    11. Patients who have had a surgical procedure unrelated to the study within 7 days prior to the administration of the drug or a significant traumatic lesion during the 4 weeks prior to starting the administration of the study drug, patients who have not recovered from the side effects of any major surgery or patients who might need major surgery during the course of the study.
    12. Pregnant or breastfeeding women. Women of childbearing potential, including women who had their last menstrual period within the last two years, must have a negative serum or urine pregnancy test in the 7 days prior to the start of the treatment.
    13. Patients who are not willing to use an adequate contraception method until 12 months after the last dose of study treatment.
    14. Patients with a serious concomitant systemic disorder (e.g., active infection, including HIV or heart disease) that is incompatible with the study (in the opinion of the investigator), history of bleeding diathesis or anticoagulant therapy (the use of low molecular weight heparin is permitted provided that it is used for prophylaxis).
    15. Inability to swallow tablets.
    16. Patients with a history of cancer that has been completely treated, with no evidence of malignant disease currently cannot be enrolled in the study if their chemotherapy was completed less than 6 months prior and/or have received a bone marrow transplant less than 2 years before the first day of study treatment.
    17. Prior treatment with cytotoxic chemotherapy for advanced NSCLC; neoadjuvant/adjuvant chemotherapy is permitted if at least 6 months have elapsed between the end of chemotherapy and the first day of study treatment.
    18. Patients who have received prior EGFR treatments for lung cancer.
    19. Patients who have received treatment with an investigational drug within 3 weeks before the first day of study treatment.
    20. Treatment with prohibited drugs within 14 days before the first day of study treatment.
    21. Any other reason that the investigator deems to be incompatible with the patient’s participation in the study.
    Se excluirá del estudio a los pacientes si cumplen ALGUNO de los criterios siguientes:
    1. Cáncer de pulmón localmente avanzado candidato para tratamiento curativo mediante cirugía radical y/o radio(quimio)terapia.
    2. Pacientes con diagnóstico de otro subtipo de cáncer de pulmón, pacientes con CPNM mixto con predominio de cáncer escamoso, o con componente de cancer de pulmón microcítico.
    3. Pacientes cuya delección o mutación en el exón 19, exón 21 (L858R, L861Q) o exón 18 (G719X) de EGFR además de la mutación T790M no hayan sido confirmadas en el laboratorio central.
    4. Haber recibido cualquier tratamiento previo para enfermedad avanzada.
    5. Segunda neoplasia activa; p.ej., paciente con diagnóstico de cáncer potencialmente letal para la que el paciente puede (pero no es obligatorio) estar recibiendo tratamiento actualmente.
    6. Pacientes con sólo una lesión tumoral medible o evaluable resecada o irradiada antes de la inclusión al estudio.
    7. Antecedentes de historia médica de Enfermedad Pulmonar Intersticial (EPI) inducida por fármacos, neumonitis rádica que requirió tratamiento esteroidal o cualquier evidencia de EPI clínicamente activa.
    8. Cualquiera de los siguientes criterios cardíacos:
    ● Intervalo QT corregido (QTc) >470 msec, obtenido de 3 ECGs en reposo, usando el valor de QTc determinado según la máquina de ECG del cribaje clínico.
    ● Cualquier anomalía clínicamente importante en el ritmo, conducción, o morfología de ECG en reposo.
    ● Cualquier factor que aumente el riesgo de prolongación de QTc o riesgo de eventos arrítmicos o muerte súbita inexplicable por debajo de los 40 años en familiares de primer grado o cualquier medicación concomitante que prolongue el intervalo QT.
    9. Metástasis no controladas activas o sintomáticas del SNC, meningitis carcinomatosa o enfermedad leptomeníngea indicada por los síntomas clínicos, edema cerebral y/o neoplasia progresiva conocidos. Los pacientes con antecedentes de metástasis del SNC o compresión medular son elegibles si han recibido tratamiento local definitivo (p. ej., radioterapia, cirugía estereotáctica) y han estado clínicamente estables sin anticonvulsivos y corticosteroides durante un mínimo de 4 semanas antes de la aleatorización.
    10. Nauseas y vómitos refractarios, enfermedad gastrointestinal crónica, imposibilidad de deglución del fármaco a estudio, o resección intestinal significativa que limite la adecuada absorción de AZD9291.
    11. Pacientes con un procedimiento quirúrgico no relacionado con el estudio antes o igual a 7 días previos a la administración del fármaco o lesión traumática significativa en las 4 semanas previas al inicio de la administración del fármaco del estudio, pacientes que no se hayan recuperado de los efectos secundarios de alguna cirugía mayor o pacientes que quizá la necesiten durante el transcurso del estudio.
    12. Mujeres embarazadas o en lactancia. Las mujeres en edad fertil, incluyendo mujeres que tuvieron la última menstruación en los dos años anteriores, deben tener un test de embarazo negativo en suero u orina en los 7 días previos al inicio del tratamiento.
    13. No usar un método contraceptivo adecuado hasta 24 semanas después de la última dosis del tratamiento de estudio.
    14. Pacientes con un trastorno sistémico concomitante grave (p. ej., infección activa, incluido el VIH, o cardiopatía) incompatible con el estudio (a criterio del investigador), antecedentes de diátesis hemorrágica o tratamiento anticoagulante (se permite el uso de heparina de bajo peso molecular siempre que se utilice con intención profiláctica).
    15. Incapacidad para deglutir comprimidos.
    16. Los pacientes con historia de cáncer tratado completamente, sin evidencia de enfermedad maligna en la actualidad, no pueden entrar en el estudio si la quimioterapia se completó hace menos de 6 meses y/o el transplante de médula ósea se completó hace menos de 2 años antes del primer día de tratamiento de estudio.
    17. Tratamiento previo con quimioterapia citotóxica para CPNM avanzado; se permite quimioterapia neoadyuvante/adyuvante si han transcurrido al menos 6 meses entre la finalización de la quimioterapia y la inclusión en el estudio.
    18. Pacientes que hayan recibido tratamientos previos contra EGFR para cancer de pulmón.
    19. Pacientes que hayan recibido tratamiento con un fármaco en investigación durante las 3 semanas antes de la inclusión en el estudio.
    20. Tratamiento con fármacos prohibidos en los últimos 14 días antes del primer día de tratamiento en el estudio.
    21. Cualquier otra razón por la cual el investigador considere que el paciente no debe participar en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is the objective response rate (ORR) which is defined as the rate of complete responses [CR] or partial responses [PR] to treatment in accordance to the guidelines of RECIST version 1.1 criteria.
    El criterio principal de valoración de este estudio es la Tasa de Respuesta Objetiva (TRO), que se define como tasa de respuestas completas [RC] o respuestas parciales [RP] al tratamiento conforme a las directrices de los criterios RECIST versión 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    An objective response should be confirmed at least 4-6 weeks after the initial response
    Una respuesta objetiva se deberá confirmar al menos 4-6 semanas después de la respuesta inicial
    E.5.2Secondary end point(s)
    Adverse events will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) of the US National Cancer Institute (NCI), version 4 [1]. Grade 3 or 4 adverse events and serious adverse events will be assessed to determine the safety and tolerability of the various combinations of drugs.
    Secondary endpoints Efficacy
    Progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), duration of response (DOR), disease control rate (DCR) and tumor shrinkage (TS) will be determined.
    PFS is defined as the time from treatment start to death or disease progression, assessed by the investigator per RECIST v1.1.
    OS is defined as the time from treatment start to death due to any cause or until the end of the previously determined follow-up period, which in this study is of 78 weeks.
    TTF is defined as the time from treatment start to the time at which the patient discontinues treatment due to any cause, including disease progression assessed by the investigator as per RECIST v1.1, toxicity, death or at the patient’s request.
    DOR is defined as the time from start of the treatment response to disease progression or death in those patients who show an objective response as per RECIST 1.1 criteria.
    DCR is defined as the sum of complete responses (CR) + partial responses (PR) + stable disease (SD).
    TS is defined as the percentage of tumor shrinkage with respect to the baseline measurements as per RECIST v1.1.
    Secondary endpoints Molecular aspects
    Correlation ratio of mutational status and documented clinical response.
    A progress curve showing the EGFR mutational status (including the T790M mutation) in plasma and serum longitudinally.
    Percentage levels of BIM mRNA as well as mRNA levels of other biomarkers related to EGFR TKI response.
    Percentage of patients with mutations at the site of covalent binding to the drug (C797) or other mutations in tissue and correlation ratio of documented clinical response
    Criterio principal de valoración: El criterio principal de valoración de este estudio es la Tasa de Respuesta Objetiva (TRO), que se define como tasa de respuestas completas [RC] o respuestas parciales [RP] al tratamiento conforme a las directrices de los criterios RECIST versión 1.1. Una respuesta objetiva se deberá confirmar al menos 4-6 semanas después de la respuesta inicial.

    Criterio secundario de valoración. Seguridad
    Los acontecimientos adversos se evaluarán mediante los criterios terminológicos comunes para acontecimientos adversos, Common Terminology Criteria for Adverse Events (CTCAE) del Instituto Nacional de Oncología estadounidense (NCI), versión 4 [1]. Los acontecimientos adversos de grado 3 y 4 y los acontecimientos adversos graves se evaluarán para determinar la seguridad y tolerabilidad de las diferentes combinaciones farmacológicas.

    Criterios secundarios de valoración. Eficacia
    Se determinarán la Supervivencia Libre de Progresión (SLP), la Supervivencia Global (SG), el Tiempo hasta el Fracaso del Tratamiento (TFT), el Tiempo de Duración de la Respuesta (TDR), la Disminución del Tamaño del Tumor (DDT) y la Tasa de Control de la Enfermedad (TCE).

    La SLP se define como el tiempo desde el inicio del tratamiento hasta la muerte o la progresión de la enfermedad, evaluada por el investigador conforme a los RECIST v1.1.
    La SG se define como el tiempo desde el inicio del tratamiento hasta la muerte por cualquier causa o hasta el máximo de tiempo de seguimiento que se determine, que en este estudio será de 78 semanas.
    El TFT se define como el tiempo desde el inicio del tratamiento hasta la progresión de la enfermedad, evaluada por el investigador conforme a los RECIST v1.1.
    El TDR se define como el tiempo desde el inicio de la respuesta del tratamiento hasta la progresión o muerte de aquellos pacientes que presentan respuesta objetiva según criterios RECIST 1.1.
    La DTT se define como el porcentaje de reducción tumoral respecto a las medidas basales según los criterios RECIST v1.1.
    La TCE se define como la suma de respuestas completas (RC) + respuestas parciales (RP) + enfermedad estable (EE).


    Criterios secundarios de valoración. Aspectos moleculares
    Indice de correlación entre el estado mutacional y la respuesta clínica documentada.
    Curva de evolución del estado mutacional de EGFR (incluída la T790M) de forma longitudinal en plasma y suero
    Porcentaje de los niveles de mRNA de BIM así como los niveles de mRNA de otros biomarcadores relacionados con la respuesta a los TKI de EGFR.
    Porcentaje de pacientes con mutaciones en el sitio de union covalente al fármaco (C797) u otras mutaciones en tejido e índice de correlación con la respuesta clínica documentada.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Since the first dose administration until Patient complete the study (or withdraw for any reason)
    Desde la primera administración del fármaco del estudio hasta que el paciente complete el estudio ( o sea retirado del estudio por cualquier razón)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic 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 No
    E.8.1.1Randomised No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned7
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The post-treatment follow-up period will last up to 78 weeks from the time of the first admistered dose.
    El periodo de seguimiento tras tratamiento continuará hasta un máximo de 78 semanas después de la primera dosis del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    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: 73
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 73
    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 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 state73
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 73
    F.4.2.2In the whole clinical trial 73
    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)
    As the IMP is authorized but not yet marketed, after Last Study Visit, in case the patient continues with the study treatment without progression or toxicity, the patient will continue with the treatment of the study until the IMP will be marketed and after that, they will be able to continue with it as per standard of care with marketed products.
    Como el producto en investigación todavía no ha sido comercializado, tras la ultima visita del paciente en el estduio, si el paciente continua en tratamiento libre de progresión ni toxicidad, el paciente continuará con la medicación del estudio hasta que esté disponible comercializada. Una vez comercializada, el paciente seguirá en tratamiento según la práctica clínica habitual en su centro.
    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 Decision2016-07-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-04
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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