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    Summary
    EudraCT Number:2014-003295-23
    Sponsor's Protocol Code Number:D4193C00001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-02-09
    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 number2014-003295-23
    A.3Full title of the trial
    A Phase II, Multi-Center, Single-Arm, Global Study of MEDI4736 Monotherapy in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN).
    Estudio de fase II, global, multicéntrico, de un único brazo de tratamiento de monoterapia con MEDI4736 en pacientes con carcinoma de células escamosas de cabeza y cuello recidivante o metastásico.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a study of MEDI4736 monotherapy in patients with head and neck cancer, who have failed a prior platinum containing treatment.
    Un estudio de MEDI4736 en monoterapia en pacientes con cancer de cabeza y cuello a los que no les funcionó una terapia con platino.
    A.4.1Sponsor's protocol code numberD4193C00001
    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 pointClinical Trial Transparency
    B.5.3 Address:
    B.5.3.1Street AddressKarlebyhus, Astraallén
    B.5.3.2Town/ citySödertälje
    B.5.3.3Post code151 85
    B.5.3.4CountrySweden
    B.5.4Telephone number900 811 335
    B.5.6E-mailClinicalTrialTransparency@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 nameMEDI4736
    D.3.2Product code MEDI4736
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot applicable
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.9.3Other descriptive nameMEDI4736
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Recurrent or metastatic PD-L1-positive squamous cell carcinoma of the head and neck (SCCHN).
    Carcinoma de células escamosas de cabeza y cuello recidivante o metastásico PD-L1 positivo.
    E.1.1.1Medical condition in easily understood language
    Head and neck cancer.
    Cáncer de cabeza y cuello.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10067821
    E.1.2Term Head and neck cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of MEDI4736 monotherapy in terms of objective response rate (ORR).
    Evaluar la eficacia de la monoterapia con MEDI4736 en cuanto a TRO.
    E.2.2Secondary objectives of the trial
    To further assess the efficacy of MEDI4736 monotherapy in terms of objective response rate (ORR), duration of response (DoR), disease control rate (DCR), deep sustained response (DSR), progression-free survival (PFS), and overall survival (OS).
    To explore symptoms and health-related quality of life (QoL) in patients treated with MEDI4736 monotherapy using the EORTC 30-item core quality of life questionnaire, version 3 (QLQ-C30 v3) and the 35-item head and neck quality of life questionnaire (H&N35) module.
    To assess the safety and tolerability profile of MEDI4736 monotherapy
    Evaluar la eficacia de la monoterapia con MEDI4736 en cuanto a TRO, DdR, TCE, RPI, SLP y SG.
    Explorar síntomas y CdV relacionada con la salud en pacientes tratados con monoterapia con MEDI4736 por medio del CCV-C30 v3 de la EORTC y del módulo CC35.
    Evaluar el perfil de seguridad y tolerabilidad de la monoterapia con MEDI4736.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    AstraZeneca intends to perform genetic research in the MEDI4736 clinical development program to explore how genetic variations may affect the clinical parameters associated with this drug. Collection of DNA samples from populations with well-described clinical characteristics may lead to improvements in the design and interpretation of clinical trials and, possibly, to genetically guided treatment strategies.
    The objective of this research is to collect and store DNA, derived from a blood sample, for future exploratory research into genes/genetic variations that may influence response, ie,
    distribution, safety, tolerability, and efficacy of MEDI4736, and/or susceptibility to SCCHN.
    All enrolled patients who take part in the main study will be asked to participate in this genetic research. Participation is voluntary. For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described in the main body of the Clinical Study Protocol and provide informed consent for the genetic sampling and analyses.
    Blood samples will ideally be collected during the screening/baseline period. If for any reason the sample is not drawn during the screening/baseline period, it should be taken as soon as possible, but not later than the last study visit. Only 1 sample should be collected per patient for genetics during the study.
    AstraZeneca pretende realizar un estudio genético dentro del programa de desarrollo clínico de MEDI4736 para explorar cómo las variaciones genéticas pueden afectar a los parámetros clínicos asociados a este fármaco. La recopilación de muestras de ADN de poblaciones con características clínicas bien descritas podrían mejorar el diseño y la interpretación de los ensayos clínicos y, posiblemente, de las estrategias de tratamiento genético.
    El objetivo de este estudio es recoger y almacenar ADN de muestras de sangre para futuras investigaciones de exploración sobre la variación génica y genética que pueda influir en la respuesta (distribución, seguridad, tolerabilidad y eficacia) de MEDI4736 y/o en la susceptibilidad al CCECC.
    Se preguntará a todos los pacientes inscritos que participen en el estudio principal si desean participar en este estudio genético. La participación es voluntaria. Para ser incluidos en este estudio genético, los pacientes deberán cumplir todos los criterios de
    inclusión descritos en el cuerpo principal del protocolo de estudio clínico y proporcionar un consentimiento informado para la obtención de muestras genéticas y análisis.
    De ser posible, las muestras de sangre se recogerán durante el período de selección/inicial y si, por algún motivo, la muestra no se extrae durante ese período, se extraerá lo antes posible, siendo el límite la última visita del estudio. Durante el estudio solo se recogerá una muestra por paciente.
    E.3Principal inclusion criteria
    1. Age ?18 years at the time of screening
    2. Written informed consent and any locally required authorization obtained from the patient/legal
    representative prior to performing any protocol-related procedures, including screening evaluations
    3. Histologically confirmed recurrent or metastatic SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) not amenable to therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Patients who refuse radical resection are eligible.
    4. Tumor progression or recurrence during or after treatment with 1 platinum containing regimen for recurrent or metastatic disease. Patients who have only received chemo-radiation therapy for locally advanced disease are not eligible.
    5. Able and willing to give valid written consent to undergo a fresh tumor biopsy for the purpose of screening for this clinical trial or to provide an available archival tumor sample taken less than 3 months ago if a fresh tumor biopsy is not feasible with an acceptable clinical risk. Tumor lesions used for fresh biopsies should not be the same lesions used as RECIST target lesions, unless there are no other lesions suitable for biopsy.
    6. Confirmed PD-L1-positive SCCHN by a specified IHC assay on a recent sample (<3 months) or fresh tumor biopsy.
    7. WHO performance status of 0 or 1 at enrollment.
    8. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ?10 mm in the longest diameter (except lymph nodes which must have a short axis ?15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. Lesions in a previously irradiated field can be used as measurable disease provided that there has been demonstrated progression in the lesion.
    9. Patients must have no prior exposure to immune-mediated therapy, including but
    not limited to other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies,
    excluding therapeutic anticancer vaccines.
    10. Adequate organ and marrow function as defined below:
    - Hemoglobin ?9 g/dL
    - Absolute neutrophil count?1500/mm3
    - Platelet count ?100000/mm3
    - Serum bilirubin ?1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert`s syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician.
    - ALT and AST ?2.5 × ULN; for patients with hepatic metastases, ALT and AST ?5 × ULN
    - Calculated creatinine clearance ?40 mL/min as determined by Cockcroft-Gault (using actual body weight)
    11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
    The following age-specific requirements apply:
    - Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and folliclestimulating hormone levels in the post-menopausal range for the institution.
    - Women ?50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral ophorectomy or hysterectomy).
    1. Tener ?18 años en el momento de la selección.
    2. El paciente o su representante legan deberán entregar el consentimiento informado por escrito y la autorización local en caso necesario (como la Ley de responsabilidad y portabilidad de seguros sanitarios en EE. UU. o la Directiva de privacidad de datos de la
    Unión Europea [UE] en la UE) antes de realizar ningún procedimiento del protocolo, incluidas las evaluaciones de selección.
    3. Tener CCECC recidivante o metastásico confirmado (cavidad bucal, orofaringe, hipofaringe o laringe) no susceptible de tratamiento curativo (cirugía o radioterapia con o sin quimioterapia). Los pacientes que rechacen la resección radical serán aptos.
    4. Mostrar progresión o recidiva tumoral durante o después de una pauta de tratamiento con platino para enfermedad recidivante o metastásica. Los pacientes que solo recibieron terapia de quimio-radiación para la enfermedad localmente avanzada no son elegibles.
    5. Poder y querer dar consentimiento válido por escrito para someterse a una biopsia tumoral reciente a efectos de selección de este ensayo clínico o proporcionar una muestra tumoral de archivo tomada menos de 3 meses antes si la biopsia no fuese factible dado su riesgo. Las lesiones tumorales usadas en las biopsias recientes no serán las mismas que las de los RECIST a menos que no haya otras lesiones adecuadas para la biopsia.
    6. Tener CCECC positivo en PD-L1 confirmado mediante un ensayo de IHC específico de una muestra reciente (< 3 meses) o biopsia tumoral reciente.
    7. Tener un estado funcional de la Organización Mundial de la Salud (OMS) de 0 o 1 en el momento de la inscripción.
    8. Tener al menos una lesión, no irradiada previamente, que se pueda medir de forma precisa en la visita inicial con ?10 mm de diámetro máximo (excepto los nodos linfáticos, que deben tener un eje corto de ?15 mm) mediante TAC o RM y que sea apta para realizar diversas mediciones precisas según las directrices RECIST 1.1. Las lesiones en un campo irradiado previamente se pueden utilizar como enfermedad cuantificable siempre que se pueda demostrar una progresión de la lesión.
    9. Los pacientes no deben haber estado expuestos a tratamiento inmunomediado, incluidos, entre otros, anticuerpos anti-CTLA-4, anti-PD-1, anti-PD-L1 o anti-PD-L2, excluidas las vacunas antineoplásicas.
    10. Deberán tener unas funciones adecuadas de órganos y médula:
    -Hemoglobina ?9 g/dL
    -Recuento absoluto de neutrófilos ?1500/mm3
    -Recuento de trombocitos ?100.000/mm3
    -Bilirrubina sérica ?1,5× límite superior de la normalidad (LSN); esto no se aplicará a pacientes con síndrome de Gilbert confirmado (hiperbilirrubinemia persistente o recidivante [predominantemente bilirrubina no conjugada] a falta de pruebas de hemólisis o insuficiencia hepática), que podrán participar tras consultar con su médico.
    -ALT y AST ?2,5 × LSN; para pacientes con metástasis hepáticas, ALT y AST ?5 × LSN
    -Depuración de creatinina calculada ?40 mL/min según Cockcroft-Gault (con el peso corporal real)
    11. Mostrar un estado posmenopáusico o una prueba de embarazo negativa en el caso de pacientes premenopáusicas. Se considerarán mujeres posmenopáusicas las que muestran amenorrea durante 12 meses sin una causa médica alternativa. Se aplicarán los siguientes
    requisitos específicos por edad:
    -Mujeres de <50 años que se considerarían posmenopáusicas de mostrar amenorrea durante 12 meses o más tras la suspensión de tratamientos hormonales exógenos y si poseen niveles de lutropina y gonadoliberina en el intervalo posmenopáusico de la institución.
    -Mujeres de ?50 años que se considerarían posmenopáusicas de mostrar amenorrea durante 12 meses o más tras la suspensión de todo tratamiento hormonal exógeno, que hayan sufrido una oforectomía por radiación con la última menstruación hace más de
    un año, menopausia por quimioterapia con un intervalo de más de un año desde la última menstruación o esterilización quirúrgica (oforectomía bilateral o histerectomía).
    E.4Principal exclusion criteria
    1. Histologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck (eg, paranasal cavity), patients with squamous cell carcinoma of the head and neck of unknown primary, and non-squamous histologies (eg, nasopharynx or salivary gland).
    2. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. Note: Local treatment of isolated lesions for palliative intent is acceptable (eg, local surgery or radiotherapy).
    3. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment.
    4. Receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, targeted therapy, biologic therapy, mAbs, etc) within 21 days prior to the first dose of study treatment. If sufficient washout time has not occurred due to the schedule or PK properties of an agent, a longer washout period will be required, as agreed upon by AstraZeneca and the Investigator.
    5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
    6. Any unresolved toxicity NCI CTCAE Grade ?2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criterion
    - Patients with Grade ?2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician.
    - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with MEDI4736 (eg, hearing loss) may be included after consultation with the Study Physician.
    7. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736. The following are exceptions to this criterion:
    - Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection)
    - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    - Steroids as pre-medication for hypersensitivity reactions (eg, CT scan pre-medication)
    8. History of allogeneic organ transplantation
    9. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn´s disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves` disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
    - Patients with vitiligo or alopecia
    - Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
    10. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness or social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs from MEDI4736 , or compromise the ability of the patient to give written informed consent
    11. Other malignancy within 5 years except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin, or ductal carcinoma in situ of the breast that has been surgically cured
    12. Patients with brain metastases, spinal cord compression, a history of leptomeningeal
    carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Investigator, may cause significant symptoms if an inflammatory reaction occurs
    13. History of active primary immunodeficiency
    14. Known history of previous clinical diagnosis of tuberculosis
    15. Active infection including hepatitis B, hepatitis C, or human immunodeficiency
    virus (HIV)
    16. Receipt of live, attenuated vaccine within 28 days prior to the first dose of MEDI4736. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of MEDI4736.
    17. Female patients who are pregnant or breast-feeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of MEDI4736
    18. Known allergy or hypersensitivity to MEDI4736 or any excipient
    19. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of patient safety or study results
    1. Carcinoma de células escamosas histológicamente confirmado en alguna otra localización principal de cabeza y cuello (como seno paranasal), pacientes con carcinoma de células escamosas de cabeza y cuello de lesión primaria desconocida e histologías no escamosas (como nasofaringe o glándula salival).
    2. Quimioterapia, PI o tratamientos biológicos u hormonales simultáneos para el cáncer. Se acepta el uso simultáneo de tratamientos hormonales para problemas no oncológicos (como tratamiento de reemplazo hormonal). Nota: se acepta el tratamiento
    paliativo local de lesiones aisladas (como cirugía local o adioterapia).
    3. Reciben tratamiento oncológico en investigación en los 28 días o 5 semividas, lo que sea mayor, anteriores a la primera dosis del tratamiento del estudio.
    4. Última dosis de un tratamiento oncológico (comercializado) aprobado (quimioterapia, tratamiento selectivo, tratamiento biológico, AM, etc.) en los 21 días anteriores a la primera dosis del tratamiento del estudio. Si no ha habido un tiempo de lavado suficiente dado el programa o las propiedades FC de un agente, será necesario un período de lavado mayor que será acordado por AstraZeneca y el investigador.
    5. Se someten a una cirugía mayor (según la definición del investigador) en los 28 días anteriores a la primera dosis del PI. Nota: se acepta la cirugía local paliativa de lesiones aisladas.
    6. Presentan alguna toxicidad no resuelta de Grado ? 2 según los CTCAA del ION de tratamientos oncológicos anteriores a excepción de alopecia, vitiligo y los valores analíticos definidos en los criterios de inclusión.
    -Los pacientes con neuropatía de Grado ?2 se evaluarán de forma individual y podrían participar tras consultarlo con el médico del estudio.
    -Los pacientes con toxicidad irreversible que no se espera que empeore con el tratamiento con MEDI4736 (como pérdida auditiva) podrían participar tras consultarlo con el médico del estudio.
    7. Utilizan o han utilizado fármacos inmunodepresores en los 14 días anteriores a la primera dosis de MEDI4736. Este criterio presenta las siguientes excepciones:
    -Esteroides tópicos intranasales inhalados o inyecciones locales de esteroides (como inyecciones intrarticulares).
    -Corticoesteroides sistémicos a dosis fisiológicas que no superen los 10 mg/día de prednisona o equivalente.
    -Esteroides como premedicación para reacciones de hipersensibilidad (premedicación para TAC).
    8. Tienen un historial de transplante de órganos alogénico.
    9. Padecen o han padecido trastornos autoinmunes o inflamatorios (incluidos enteropatía inflamatoria [como colitis o enfermedad de Crohn], diverticulitis a excepción de un episodio previo resuelto o diverticulosis, celiaquía, síndrome del colon irritable y otros
    trastornos gastrointestinales crónicos graves con diarrea; lupus eritematoso sistémico; granulomatosis de Wegener [granulomatosis con poliangitis]; miastenia grave; enfermedad de Graves; artritis reumatoide, hipofisitis, uveítis, etc.) en los 3 años anteriores al inicio del tratamiento. Este criterio presenta las siguientes excepciones:
    -Pacientes con vitiligo o alopecia.
    -Pacientes con hipotiroidismo (p. ej., tras la enfermedad de Hashimoto) estable con reemplazo hormonal o psoriasis sin tratamiento sistémico.
    10. Presentan alguna enfermedad intercurrente no controlada como, entre otras, infecciones activas, insuficiencia cardíaca congestiva sintomática, hipertensión no controlada, angina de pecho inestable, arritmia cardíaca, neumopatía intersticial o trastornos psiquiátricos o
    situaciones sociales que limiten el cumplimiento de los requisitos del estudio, aumenten considerablemente el riesgo de incurrir en AA de MEDI4736 o comprometan la capacidad del paciente para dar su consentimiento informado por escrito.
    11. Padecen otra neoplasia maligna en un plazo de 5 años, excepto aquellas no invasivas como el carcinoma cervical localizado, el carcinoma cutáneo no melanoma o el carcinoma ductal de la mama localizado curados quirúrgicamente.
    12. Pacientes con metástasis cerebrales, compresión de la médula espinal, historial de carcinomatosis subaracnoidea o afectación de otra localización anatómica que, en opinión del investigador, pueda generar síntomas significativos en caso de reacción inflamatoria.
    13. Poseen un historial de inmunodeficiencia primaria activa.
    14. Fueron diagnosticados de tuberculosis anteriormente.
    15. Tienen infecciones activas, incluidas hepatitis B, hepatitis C o virus de la inmunodeficiencia humana (VIH).
    16. Reciben una vacuna con microbios vivos atenuada en los 28 días anteriores a la primera dosis de MEDI4736. Nota: los pacientes que participen no se deberán vacunar durante el estudio ni hasta pasados 30 días de la última dosis de MEDI4736.
    17. Pacientes embarazadas o en fase de lactancia y todos los pacientes en edad reproductiva que no deseen utilizar métodos anticonceptivos eficaces entre la selección y los 90 días posteriores a la última dosis de MEDI4736.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the objective response rate (ORR). ORR is defined as the number (%) of patients with a confirmed overall response of complete response (CR) or partial response (PR) and will be based on all treated patients who have measurable disease at baseline per ICR.
    El criterio de valoración principal es la TRO. La TRO (por los RECIST 1.1 según la valoración de la RCI) se define como el número (%) de pacientes con respuesta global confirmada de RC o RP y se basará en todos los pacientes tratados con enfermedad cuantificable en la visita inicial por RCI. Por tanto, si la RCI detecta algún paciente que no tenga enfermedad cuantificable en la visita inicial, entonces el análisis de la TRO a partir de los datos de la RCI excluirá a ese paciente y el denominador serán todos los pacientes tratados que tengan enfermedad cuantificable en la visita inicial por RCI.
    E.5.1.1Timepoint(s) of evaluation of this end point
    A confirmed response of confirmed or partial response means that a response of complete or partial response is recorded at one visit and confirmed by repeat imaging not less than 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and confirmed or partial response confirmation visit. Therefore, data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of objective response rate.
    Una respuesta de RC/RP confirmada significa que se ha registrado una respuesta de RC/RP en una visita y que se ha confirmado mediante la repetición de la prueba al menos 4 semanas después de la visita en la que se observó por primera vez la respuesta sin indicios de progresión entre la visita inicial y la de confirmación de la RC/RP. Por tanto, en la evaluación de la TRO se incluirán los datos
    obtenidos hasta la progresión o hasta la última valoración evaluable cuando no haya progresión.
    E.5.2Secondary end point(s)
    1. Duration of response (DoR) - time from the date of first documented response until the first date of documented progression or death in the absence of disease progression.
    2. Disease control rate (DCR) - percentage of patients who have a best objective response (BoR) of confirmed or partial response in the first 4 or 12 months or who have demonstrated stable disease (SD) for a minimum interval of 16 or 52 weeks following the start of treatment.
    3. Deep sustained response (DSR) - the percent of patients with a 30% decrease in the sum of target lesions that has been sustained for 12 months or a 50% decrease in the sum of target lesions that has been sustained for 6 months.
    4. Progression-free survival (PFS) - time from the date of first dose until the date of objective disease progression or death.
    5. Overall survival (OS) - time from the date of enrollment until death due to any cause.
    6. Best objective response (BoR) - the best response a patient has had during their time in the study up until RECIST or confirmed progression or the last evaluable assessment.
    1. Duración de la respuesta (DdR) - tiempo transcurrido desde la fecha de la primera respuesta documentada hasta la primera fecha de progresión documentada o la defunción a falta de progresión de la enfermedad.
    2. Tasa de control de enfermedad (TCE) - porcentaje de pacientes que presenta una mejor respuesta objetiva (MRO) que la RC o la RP en los primeros 4 o 12 meses respectivamente, o que ha presentado EE durante un intervalo mínimo de 16 o 52 semanas respectivamente desde el inicio del tratamiento del estudio.
    3. Respuesta prolongada intensa (RPI) - número (%) de pacientes con una reducción del 30 % en la suma de las lesiones objetivo que se haya mantenido durante 12 meses o con una reducción del 50 % en la suma de las lesiones objetivo que se haya mantenido durante 6 meses.
    4. Supervivencia libre de progresión (SLP) - tiempo transcurrido desde la fecha de la primera dosis hasta la fecha de la progresión objetiva de la enfermedad o la muerte.
    5. Supervivencia global (SG) - tiempo transcurrido entre la fecha de la inscripción y la defunción por cualquier causa.
    6. Mejor respuesta objetiva (MRO) - la mejor respuesta que un paciente ha tenido desde que está en el estudio y hasta la progresión según los RECIST o hasta la progresión confirmada, o la última valoración evaluable.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. DoR - time of the initial response will be defined as the latest of the dates contributing towards the first visit response of PR or CR.
    2. DCR - first 4 or first 12 months.
    3. DSR - 12 months for 30% decrease and 6 months for 50% decrease.
    4. PFS time will be derived based on scan/assessment dates.
    5. OS - Survival calls will be made in the week following the date of data cut-off for the analysis, and if patients are confirmed to be alive or if the death date is post the data cut-off date, these patients will be censored at the date of data cut-off.
    6. BoR - for deaths occuring ?17 weeks after enrollment BoR will be assigned to the progressive disease (PD) category and for deaths occuring >17 weeks after enrollment BoR will be assigned to the not evaluable (NE) category.
    1.DdR-la más reciente de las fechas que hayan contribuido a la primera respuesta de RC o RP en las visitas.
    2.TCE-primeros 4 o primeros 12 meses.
    3.RPI-12 meses para una reducción del 30% y 6 meses para una del 50%.
    4.El tiempo de SLP se calculará a partir de las fechas de las pruebas/evaluaciones.
    5.SG-las llamadas de supervivencia se harán la semana siguiente a la fecha valor de corte de datos. Si se confirma supervivencia o la fecha de defunción es posterior a la fecha valor de corte de datos,los pacientes serán censurados en la fecha valor de corte de datos.
    6.MRO-si la defunción se produce ?17 semanas tras la inscripción, se asignará la MRO a la categoría de progresión (EP). Si se produce > 17 semanas tras la fecha de inscripción, se asignará la MRO a la categoría de NE.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic 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 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.8.2.4Number of treatment arms in the trial1
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    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
    Belgium
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Spain
    United Kingdom
    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
    Last visit of the last patient undergoing the study.
    Última visita del último paciente del estudio.
    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 months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 67
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 112
    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)
    After the final analysis, AstraZeneca will continue to supply open-label drug to patients receiving MEDI4736 as long as, in the Investigator?s opinion, the patient is gaining clinical benefit from active treatment. Patients will only be able to restart treatment once; thus, a maximum of two 12-month treatment periods will be allowed.
    Tras el análisis final, AstraZeneca seguirá suministrando el fármaco abierto a los pacientes que reciban MEDI4736 siempre que, en opinión del investigador, el paciente saque provecho del tratamiento activo. Los pacientes solo podrán reiniciar el tratamiento una vez, por lo que solo se permitirá un máximo de dos períodos de tratamiento de 12 meses.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-08
    P. End of Trial
    P.End of Trial StatusCompleted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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