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    Summary
    EudraCT Number:2017-002359-27
    Sponsor's Protocol Code Number:D5161C00003
    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:2017-10-02
    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 number2017-002359-27
    A.3Full title of the trial
    A Multicentre, Open-label, Single-arm, Molecular Profiling Study of Patients with EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated with Osimertinib
    Estudio multicéntrico, abierto y de un solo grupo, del perfil molecular de pacientes con cáncer de pulmón no microcítico con mutación del EGFR, localmente avanzado o metastásico, tratados con osimertinib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A molecular profiling study of osimertinib in patients with EGFR mutated lung cancer who have not yet received any drug therapy for advanced lung cancer
    Estudio del perfil molecular de osimertinib en pacientes con cáncer de pulmón con mutación del EGFR que aún no han recibido ningún tratamiento para cancer de pulmón avanzado
    A.3.2Name or abbreviated title of the trial where available
    ELIOS
    ELIOS
    A.4.1Sponsor's protocol code numberD5161C00003
    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
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street AddressUSA
    B.5.3.2Town/ cityUSA
    B.5.3.3Post codeUSA
    B.5.3.4CountryUnited States
    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 Yes
    D.2.1.1.1Trade name TAGRISSO™
    D.2.1.1.2Name of the Marketing Authorisation holderAstra Zeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameOsimertinib
    D.3.2Product code AZD9291
    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 INNOsimertinib
    D.3.9.2Current sponsor codeAZD9291
    D.3.9.3Other descriptive nameOsimertininb mesylate; AZD9291 mesylate
    D.3.9.4EV Substance CodeSUB176340
    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.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 holderAstra Zeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameOsimertinib
    D.3.2Product code AZD9291
    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 INNOsimertinib
    D.3.9.2Current sponsor codeAZD9291
    D.3.9.3Other descriptive nameOsimertininb mesylate; AZD9291 mesylate
    D.3.9.4EV Substance CodeSUB176340
    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.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
    EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer not amenable to curative surgery or radiotherapy
    Cáncer de pulmón no microcítico localmente avanzado o metastásico, con mutación del EGFR, no susceptible de cirugía o radioterapia curativas
    E.1.1.1Medical condition in easily understood language
    Specific type of lung cancer called non-small cell lung cancer (NSCLC)
    Un tipo específico de cáncer de pulmón conocido como cáncer de pulmón no microcítico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 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 20.0
    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 20.0
    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 examine the genetic and proteomic profile at the point of disease progression in patients receiving osimertinib as first-line EGFR TKI therapy for EGFRm+ locally advanced or metastatic NSCLC compared to the profile prior to initiation of treatment
    Examinar el perfil genético y proteómico en el momento de la progresión de la enfermedad en pacientes tratados con osimertinib como tratamiento de primera línea con un inhibidor de la tirosina-cinasa del EGFR por cáncer de pulmón no microcítico con mutación del EGFR, localmente avanzado o metastásico, en comparación con el perfil previo al inicio del tratamiento.
    E.2.2Secondary objectives of the trial
    1) To assess the efficacy of osimertinib as first line EGFR TKI therapy for patients with EGFRm+ locally advanced or metastatic NSCLC.
    2) To assess the efficacy of osimertinib in patient subgroups defined by molecular profile, including but not limited to:
    • Positive pre-treatment T790M mutation
    • EGFR Ex19del or L858R mutation
    • EGFR Ex19del or L858R detectable in plasma-derived circulating tumour deoxyribonucleic acid (ctDNA).
    3) To further assess the efficacy of osimertinib post progression.
    4) To summarize the safety and tolerability profile of osimertinib as first-line EGFR tyrosine kinase inhibitor therapy for patients with EGFR mutation-positive locally advanced or metastatic NSCLC
    1) Evaluar la eficacia del osimertinib como tratamiento de primera línea con un inhibidor de la tirosina-cinasa del EGFR en pacientes con cáncer de pulmón no microcítico con mutación del EGFR, localmente avanzado o metastásico.
    2) Evaluar la eficacia del osimertinib en ciertos subgrupos de pacientes definidos por el perfil molecular, tales como, entre otros:
    • Presencia de la mutación T790M antes del tratamiento
    • Mutación Ex19del o L858R del EGFR
    • Mutación Ex19del o L858R del EGFR detectable en ácido desoxirribonucleico tumoral circulante en plasma
    3) Evaluar adicionalmente la eficacia del osimertinib después de la progresión de la enfermedad.
    4) Resumir el perfil de seguridad y tolerabilidad del osimertinib como tratamiento de primera línea con un inhibidor de la tirosina-cinasa del EGFR en pacientes con cáncer de pulmón no microcítico con mutación del EGFR, localmente avanzado o metastásico.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of informed consent prior to any study specific procedures (signed and dated informed consent form).
    2. Patients aged 18 years or older.
    3. Patients with histological confirmation of locally advanced or metastatic, non squamous NSCLC who are not candidates for local curative treatment.
    4. Patients with M1 stage according to the Tumour, Node, and Metastasis Classification of Malignant Tumours (TNM) version 7 including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease that is not a candidate for curative treatment (including patients who progress after chemo radiotherapy in stage III disease).
    5. Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be associated with EGFR TKI sensitivity before treatment by local assessment.
    6. Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Patients with asymptomatic and stable central nervous system (CNS) metastases are eligible for the study; treatment with low dose corticosteroids is allowed, but is not a requirement for eligibility. 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 increasing doses of corticosteroids for a minimum of 2 weeks prior to the first day of study treatment.
    7. Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the primary tumour or metastatic tumour tissue, within the 60 days prior to study entry and at or after RECIST 1.1-defined progression.
    8. WHO performance status 0-1.
    9. Life expectancy ≥12 weeks.
    10. Adequate coagulation: international normalised ratio (INR) ≤1.5 for patients on anti-coagulation therapy.
    11. Capacity to swallow.
    12. Patients able to complete study and within geographical proximity allowing for adequate follow up.
    13. Resolution of all acute toxic effects of previous anticancer therapy (which can only be adjuvant or neoadjuvant) or surgical interventions to grade 1 according to the National Cancer Institute (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).
    14. Female patients should be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of childbearing potential or must have evidence of nonchildbearing potential by fulfilling one of the following criteria at screening:
    - Postmenopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments;
    - Female patients under 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range for the institution;
    - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation;
    15. Male patients should be willing to use barrier contraception.
    1. Paciente que otorga su consentimiento informado (firmado y fechado) antes de la práctica de cualquier procedimiento del estudio.
    2. Paciente de 18 o más años de edad.
    3. Paciente con cáncer de pulmón no microcítico, no epidermoide, localmente avanzado o metastásico, confirmado histológicamente, que no es candidato para tratamiento curativo local.
    4. Paciente con enfermedad M1 de la Tumour, Node, and Metastasis Classification of Malignant Tumours (TNM), versión 7, incluidos M1a (derrame maligno) o M1b (metástasis a distancia), o enfermedad localmente avanzada que no es candidato para tratamiento curativo (incluidos los pacientes con progresión de la enfermedad tras quimio-radioterapia en estadio III).
    5. En su estudio local, antes del tratamiento, paciente con deleción o mutación del EGFR (observada en biopsia tumoral o en plasma) que se sabe sensible a los inhibidores de la tirosina cinasa del EGFR.
    6. Presencia de enfermedad medible o evaluable (de acuerdo a los criterios RECIST 1.1). Son elegibles para el estudio los pacientes con metástasis en sistema nervioso central de carácter asintomático y estable; se permite su tratamiento con corticosteroides a dosis bajas, aunque no supone un requisito para la elegibilidad. Son elegibles los pacientes con historia de metástasis en sistema nervioso central o compresión de médula espinal si han recibido tratamiento local final (por ejemplo, radioterapia, cirugía estereotáctica) y han permanecido clínicamente estables, sin anticonvulsivantes ni dosis crecientes de corticosteroides, durante un mínimo de 2 semanas antes del primer día del tratamiento del estudio.
    7. Posibilidad de obtener una muestra de tejido suficiente, ya sea mediante biopsia o resección quirúrgica del tumor primitivo o de una metástasis, en el plazo de los 60 días anteriores a la entrada en el estudio y en ocasión o tras progresión de la enfermedad según RECIST 1.1.
    8. Estado funcional de la OMS 0-1.
    9. Esperanza de vida ≥12 semanas.
    10. Coagulación adecuada: international normalised ratio (INR) ≤1,5 en los pacientes anticoagulados.
    11. Capacidad de deglutir.
    12. Paciente capaz de completar el estudio y residente en un área geográfica próxima que posibilite su seguimiento adecuado.
    13. Resolución de todos los efectos tóxicos agudos del tratamiento previo antineoplásico (que solamente podrá ser adyuvante o neoadyuvante) o quirúrgico a grado 1 de los CTCAE del National Cancer Institute (NCI) versión 4.0 (excepto en cuanto a alopecia u otro efecto secundario que el Investigador considere que no supone un riesgo para la seguridad del paciente).
    14. Si se trata de una mujer potencialmente fértil deberá estar adoptando medidas anticonceptivas altamente eficaces y arrojar un resultado negativo de una prueba de embarazo antes del inicio del tratamiento; para poder ser considerada como no potencialmente fértil deberá cumplir uno de los siguientes criterios en la selección:
    - En posmenopausia, lo que se define como mujer de más de 50 años y en amenorrea durante como mínimo 12 meses tras la suspensión de todo tipo de hormonoterapia exógena;
    - Las mujeres de menos de 50 años se considerarán en posmenopausia si han estado en amenorrea durante como mínimo 12 meses tras la suspensión de todo tipo de hormonoterapia exógena y presentan unos niveles de hormona luteinizante y de hormona folículo-estimulante en el rango posmenopáusico del Centro;
    - Documentación de esterilización quirúrgica irreversible por histerectomía, ovariectomía bilateral o salpingectomía bilateral, pero no por ligadura de trompas;
    15. Si se trata de un varón, deberá estar de acuerdo en utilizar un método anticonceptivo de barrera.
    E.4Principal exclusion criteria
    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 an EGFR exon 20 insertion.
    4. Patients with just one measurable or evaluable tumour lesion that has been resected or irradiated prior to their enrolment in the study.
    5. Second active neoplasia.
    6. Treatment with an investigational drug within five half-lives of the compound.
    7. Participation in another clinical study with an investigational product (IP) during the last 3 weeks before the first day of study treatment.
    8. Patients who have received prior immunotherapies.
    9. Patients who have received prior EGFR treatments for lung cancer.
    10. Patients who have received prior treatment with an EGFR TKI including in the adjuvant setting.
    11. Patients who have received previous treatment for metastatic or stage IV disease.
    12. 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).
    13. 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
    14. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.
    15. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
    16. Patients who have had a surgical procedure unrelated to the study within 14 days or major surgery within 1 month prior to the administration of the study drug; patients with a significant traumatic lesion (as judged by the Investigator that would risk patient safety) 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.
    17. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required corticosteroid treatment, or any evidence of clinically active interstitial lung disease.
    18. Any of the following cardiac criteria:
    - Mean resting QT interval corrected for heart rate (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value;
    - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block;
    - Any 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 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
    19. Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or leptomeningeal disease indicated by known clinical symptoms, cerebral oedema and/or progressive neoplasia.
    20. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
    21. Inadequate bone marrow reserve or organ function as demonstrated by the laboratory values.
    22. Female patients who are breastfeeding.
    23. Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4 (at least 3 weeks prior). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
    24. Patient unwilling to undergo a biopsy at the time of disease progression.
    25. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib
    1. Cáncer de pulmón localmente avanzado candidato para tratamiento curativo mediante cirugía radical y/o radio(quimio)terapia.
    2. Pacientes diagnosticados de otro subtipo de cáncer de pulmón, pacientes con cáncer de pulmón no microcítico mixto con predominio epidermoide, o con cualquier componente de cáncer de pulmón microcítico. 3. Pacientes con una inserción en el exón 20 del EGFR. 4. Pacientes con sólo una lesión tumoral medible o evaluable que se ha resecado o irradiado antes de su entrada en el estudio. 5. Segunda neoplasia activa. 6. Tratamiento con un fármaco en fase de investigación en el plazo de cinco semividas de dicho producto. 7. Participación en otro estudio clínico con un fármaco en fase de investigación en el plazo de las 3 últimas semanas anteriores al primer día del tratamiento del estudio. 8. Pacientes que han recibido inmunoterapias previas. 9. Pacientes que han recibido tratamientos previos dirigidos al EGFR por cáncer de pulmón. 10. Pacientes que han recibido tratamiento previo con un inhibidor de la tirosina cinasa del EGFR, incluido en el marco adyuvante. 11. Pacientes que han recibido tratamiento previo por enfermedad metastásica o en estadio IV. 12. Tratamiento previo con quimioterapia citotóxica por cáncer de pulmón no microcítico avanzado (se permite la quimioterapia neoadyuvante/adyuvante si han transcurrido como mínimo 6 meses entre su fin y el primer día del tratamiento del estudio).
    13. Los pacientes con antecedentes de cáncer que se ha tratado por completo y sin evidencia actual de enfermedad maligna no podrán entrar en el estudio si su quimioterapia finalizó menos de 6 meses antes y/o han recibido un trasplante de médula ósea menos de 2 años antes del primer día del tratamiento del estudio. 14. Todo efecto tóxico del tratamiento previo no resuelto mayor de grado 1 de los CTCAE en el momento de inicio de tratamiento del estudio, con excepción de la alopecia y de la neuropatía de grado 2 por platino previo. 15. Toda evidencia de enfermedad sistémica severa o no controlada, incluidas la hipertensión no controlada y la diátesis hemorrágica activa, que, en opinión del Investigador, desaconseja la participación del paciente en el ensayo o que pudiera afectar a su cumplimiento con el protocolo, o la infección activa, incluidas las hepatitis B o C y el virus de la inmunodeficiencia humana. No se precisa descartar la presencia de enfermedades crónicas.
    16. Pacientes que se han sometido a un procedimiento quirúrgico no relacionado con el estudio en el plazo de los 14 días o a cirugía mayor en el plazo de 1 mes antes de la administración del fármaco del estudio; pacientes con traumatismo importante (que, en opinión del Investigador, pudiera afectar a la seguridad del paciente) durante las 4 semanas previas al inicio de la administración del fármaco del estudio; pacientes que no se han recuperado de los efectos secundarios de una cirugía mayor; o pacientes que puedan precisar cirugía mayor durante el curso del estudio.
    17. Antecedente de enfermedad pulmonar intersticial, enfermedad pulmonar intersticial de origen farmacológico, neumonitis por radiación que precisa tratamiento con corticosteroides, o cualquier signo de enfermedad pulmonar intersticial clínicamente activa.
    18. Cualquiera de los siguientes criterios cardíacos:
    - Valor medio del intervalo QT en reposo corregido según la frecuencia cardíaca (QTc) >470 mseg, obtenido de 3 electrocardiogramas, utilizando el valor del QTc obtenido con el electrocardiógrafo del Centro en la selección;
    - Toda anomalía clínicamente importante del ritmo, la conducción o la morfología del ECG en reposo: por ejemplo, bloqueo completo de rama izquierda, bloqueo de tercer grado y bloqueo de segundo grado;
    - Cualquier factor que pueda aumentar el riesgo de prolongación del QTc o de fenómenos arrítmicos, como insuficiencia cardíaca, hipopotasemia, síndrome de QT largo congénito, antecedentes familiares de síndrome de QT largo o muerte súbita no explicada por debajo de los 40 años de edad en familiar en primer grado, o cualquier medicación concomitante que se sabe que prolonga el intervalo QT.
    19. Metástasis en sistema nervioso central no controladas, activas o sintomáticas, meningitis carcinomatosa o enfermedad leptomeníngea evidenciada por síntomas clínicos evidentes, edema cerebral y/o neoplasia cerebral en progresión. 20. Náuseas y vómitos resistentes al tratamiento, enfermedad gastrointestinal crónica, incapacidad de deglución del producto del estudio o resección intestinal importante previa que pueda impedir la absorción adecuada del osimertinib. 21. Reserva de médula ósea o función orgánica inadecuadas, según se desprende de la analítica.
    22. Mujeres que están amamantando.
    Por favor refieranse al protocolo para ver el resto de criterios de exclusión.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients with a given genetic and proteomic marker (including, but not limited to, EGFR mutations, HER2, and cMET expression and/or amplification) at the point of disease progression as defined by the Investigator
    Porcentaje de pacientes con un marcador genético y proteómico dado (como, entre otros, mutaciones del EGFR, HER2 y expresión y/o amplificación del cMET) en el momento de la progresión de la enfermedad evaluada por el investigador
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the point of disease progression
    En el momento de progresión de la enfermedad
    E.5.2Secondary end point(s)
    Progression-free survival, according to RECIST 1.1 by Investigator assessment, and other selected clinical efficacy endpoints including:
    • Objective response rate
    • Duration of response
    • Disease control rate
    • Tumour shrinkage/depth of response, defined as best change from baseline in target lesion tumour size
    • Time to treatment discontinuation or death
    • Important patient and disease characteristics
    • Time to first subsequent therapy or death
    Safety Endpoints:
    • Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0
    • Clinical chemistry, haematology and urinalysis
    • Vital signs, physical examination, body weight
    • Electrocardiogram
    • World Health Organization performance status
    Supervivencia sin progresión según RECIST 1.1 en la evaluación por el investigador y otros criterios clínicos de valoración de la eficacia elegidos, a saber:
    • Tasa de respuesta objetiva
    • Duración de la respuesta
    • Tasa de control de la enfermedad
    • Reducción del tumor/amplitud de la respuesta, definida como el mejor cambio respecto al momento basal en el tamaño de las lesiones diana tumorales
    • Tiempo hasta la retirada del tratamiento o la muerte
    • Características importantes del paciente y de la enfermedad
    • Tiempo hasta el primer tratamiento posterior o la muerte
    Criterios de valoración de la seguridad:
    • Acontecimientos adversos clasificados en grados según los Criterios Terminológicos Comunes para Acontecimientos Adversos, versión 4.0
    • Bioquímica sérica, hematología y análisis de orina
    • Constantes vitales, exploración física, peso corporal
    • Electrocardiograma
    • Estado funcional de la Organización Mundial de la Salud
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the trial
    A lo largo del 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 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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolerabilidad
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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
    Italy
    Korea, Republic of
    Malaysia
    Spain
    Taiwan
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as when the final analysis of the biopsy data is performed. If the final analysis is performed when over 80% of patients have progressed or died then this analysis may occur 48 months after the first patient in (Q3 2021).
    El fin del estudio se define por la práctica del análisis final de los datos de las biopsias. Si el análisis final se practicara cuando más del 80% de los pacientes han presentado progresión de la enfermedad o han fallecido, éste análisis podría tener lugar 48 meses después de la inclusión del primer paciente en el estudio (tercer trimestre de 2021).
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 116
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 29
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 33
    F.4.2.2In the whole clinical trial 145
    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 in accordance with the regional standard of care
    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 Decision2017-11-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-07
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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