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    Summary
    EudraCT Number:2014-003717-29
    Sponsor's Protocol Code Number:D4193C00003
    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:2015-07-02
    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 number2014-003717-29
    A.3Full title of the trial
    A Phase II, Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 Monotherapy, Tremelimumab Monotherapy, and MEDI4736 in Combination with Tremelimumab in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)
    Estudio de fase II, aleatorizado, abierto, global, multicéntrico de monoterapia con MEDI4736, monoterapia con tremelimumab y MEDI4736 en combinación con tremelimumab en pacientes con carcinoma de células escamosas de cabeza y cuello recidivante o metastásico (CCECC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of MEDI4736 Monotherapy, Tremelimumab Monotherapy, and MEDI4736 in Combination with Tremelimumab in Patients with SCCHN
    A.4.1Sponsor's protocol code numberD4193C00003
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02319044
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca AB
    B.5.2Functional name of contact 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 INNNA
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTremelimumab
    D.3.2Product code MEDI1123
    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 INNTremelimumab
    D.3.9.1CAS number 745013-19-6
    D.3.9.2Current sponsor codeMEDI1123
    D.3.9.3Other descriptive nameNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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.IMP: 3
    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 INNNA
    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.IMP: 4
    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 nameTremelimumab
    D.3.2Product code MEDI1123
    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 INNTremelimumab
    D.3.9.1CAS number 745013-19-6
    D.3.9.2Current sponsor codeMEDI1123
    D.3.9.3Other descriptive nameNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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
    Patients with recurrent or metastatic PD-L1-negative squamous cell carcinoma of the head and neck (SCCHN)
    Pacientes con carcinoma de cabeza y cuello recurrente o metastásico PD-L1 negativo (CCECC)
    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 18.0
    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 + tremelimumab combination therapy in terms of ORR
    Evaluar la eficacia de una terapia de combinación de MEDI4739 + tremelimumab en términos de tasa de respuesta objetiva.
    E.2.2Secondary objectives of the trial
    To further assess the efficacy of MEDI4736 + tremelimumab combination therapy in terms of ORR, DoR, DCR, BoR, PFS, and OS;
    To assess the efficacy of MEDI4736 + tremelimumab combination therapy compared with a) MEDI4736 monotherapy and b) tremelimumab monotherapy, in terms of ORR and PFS;
    To explore symptoms and health-related QoL in patients treated with MEDI4736 monotherapy, tremelimumab monotherapy, and MEDI4736 + tremelimumab combination therapy using the EORTC QLQ-C30 v3 and the H&N35 module
    Evaluar la eficacia de la monoterapia con MEDI4736, de la monoterapia con tremelimumab y de la terapia combinada de MEDI4736 + tremelimumab 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, con monoterapia con tremelimumab, y con la terapia de combinación de MEDI4736 + tremelimumab por medio del CCV-C30 v3 de la EORTC y del módulo CC35.
    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.
    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 + tremelimumab 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 y, si un paciente no desea participar, no incurrirá en ninguna penalización ni pérdida de beneficios, ni será excluido de otros aspectos del estudio principal.
    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. Aunque el genotipo es un parámetro estable, es preferible recoger las muestras temprano para evitar los sesgos al excluir a los pacientes que se puedan retirar dado un acontecimiento adverso, ya que sería importante incluir a dichos
    pacientes en algún análisis genético. 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; 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 curative intent of locally advanced disease are not eligible. Patients who received chemo-radiation alone as part of treatment of their recurrent disease are also 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; 6) Confirmed PD-L1-negative 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 short axis ?15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines; 9) Patients must have no prior exposure to immune-mediated therapy, including other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines. Exposure to other investigational agents may be permitted after discussion with the Sponsor; 10) Adequate organ and marrow function independent of transfusion for at least 7 days prior to screening and independent of growth factor support for at least 14 days prior to screening, defined as: Hemoglobin ?9 g/dL, Absolute neutrophil count ?1500/mm3, Platelet count ?100000/mm3, Serum bilirubin ?1.5 × the upper limit of normal (ULN), 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; 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.
    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. No podrán participar los pacientes que solo hayan recibido radioquimioterapia con intención curativa para la enfermedad localmente avanzada. Tampoco podrán participar los pacientes que hayan recibido radioquimioterapia sola como parte del tratamiento de la enfermedad recidivante.
    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 negativo en PD-L1 confirmado mediante un ensayo de IHC específico de una muestra reciente (< 3 meses) o biopsia tumoral reciente. Con independencia de la antigüedad del resultado de PD-L1, si el estado de PD-L1 del paciente ha sido evaluado mediante el ensayo Ventana como parte del proceso de selección de otro estudio de AstraZeneca/MedImmune, este resultado se podrá utilizar para determinar la aptitud, siempre que entre tanto no se haya administrado ningún tratamiento.
    Nota: La muestra negativa para el PD-L1 se determina mediante el valor de corte definido basado en menos del 25% de células tumorales con tinción de PD-L1 en membrana, de cualquier intensidad (es decir, el estado negativo de PD-L1 es inferior al 25 %).
    7. Tener un estado funcional de la 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 anticuerpos anti-CTLA-4, anti-PD-1, anti-PD-L1 o anti-PD-L2, excluidas las vacunas antineoplásicas. La exposición a otros fármacos en investigación podría ser permitida
    previa consulta con el promotor.
    10. Deberán tener unas funciones adecuadas de órganos y médula, que no dependan de haber recibido una transfusión durante al menos los 7 días previos a la selección o un tratamiento de soporte con factor de crecimiento durante al menos los 14 días previos a la selección, definidas como:
    ? 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.
    E.4Principal exclusion criteria
    1) Histologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck, patients with squamous cell carcinoma of the head and neck of unknown primary, and non squamous histologies; 2) Received more than 1 regimen for recurrent or metastatic disease; 3) Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions is acceptable; 4) Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment; 5) Receipt of last dose of an approved (marketed) anticancer therapy 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; 6) 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; 7) 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 their assigned IP may be included after consultation with the Study Physician; 8) Current or prior use of immunosuppressive medication within 14 days before the first dose of their assigned IP. The following are exceptions to this criterion: * - Intranasal, inhaled, topical steroids, or local steroid injections, ** - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent, *** - Steroids as pre-medication for hypersensitivity reactions; 9) History of allogeneic organ transplantation; 10) Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, , or other serious GI chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome; 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 stable on hormone replacement or psoriasis not requiring systemic treatment; 11) 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 tremelimumab, or compromise the ability of the patient to give written informed consent; 12) History of another primary malignancy except for: * - Malignancy treated with curative intent and with no known active disease ?5 years before the first dose of study drug and of low potential risk for recurrence, ** - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, *** - Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ; 13) Patients with history of brain metastases, spinal cord compression, or 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; 14) History of active primary immunodeficiency; 15) Known history of previous clinical diagnosis of tuberculosis; 16) Active infection including hepatitis B, hepatitis C or HIV; 17) Receipt of live, attenuated vaccine within 28 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of both IPs; 18) 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; 19) Mean QT interval corrected for heart rate ?470 ms calculated from 3 ECGs using Friderica?s Correction; 20) Known allergy or hypersensitivity to IP or any IP excipient; 21) 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. Tienen 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. Han recibido más de 1 pauta para la enfermedad recidivante o metastásica.
    3. Reciben 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).
    4. 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.
    5. Reciben la 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.
    6. Se someten a una cirugía mayor (según la definición del investigador) en los 28 días anteriores a la primera dosis del PI.
    7. 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.
    8. Utilizan o han utilizado fármacos inmunodepresores en los 14 días anteriores a la primera dosis de su PI asignado.
    9. Tienen un historial de transplante de órganos alogénico.
    10. 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 y otros trastornos GI 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.
    11. 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 de tremelimumab o comprometan la capacidad del paciente para dar su consentimiento informado por escrito.
    12. Antecedentes de otra neoplasia maligna primaria, excepto:
    - Neoplasias malignas tratadas con intención curativa, sin actividad
    conocida de la enfermedad durante ? 5 años antes de la primera dosis del fármaco del estudio y con bajo riesgo potencial de recidiva
    - Cáncer de piel diferente del melanoma o léntigo maligno tratados
    adecuadamente, sin signos de enfermedad
    - Carcinoma localizado (p. ej., carcinoma cervical localizado) tratado
    adecuadamente, sin signos de enfermedad
    13. Pacientes con historial de metástasis cerebrales, compresión de la médula espinal o carcinomatosis subaracnoidea o afectación de otra localización anatómica que, en opinión del investigador, pueda generar síntomas significativos en caso de reacción inflamatoria.
    14. Poseen un historial de inmunodeficiencia primaria activa.
    15. Fueron diagnosticados de tuberculosis anteriormente.
    16. Tienen infecciones activas, incluidas hepatitis B, hepatitis C o virus de la inmunodeficiencia humana (VIH).
    17. Reciben una vacuna con microbios vivos atenuada en los 28 días anteriores a la primera dosis del PI.
    18. 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 para los aleatorizados al brazo de monoterapia con MEDI4736 o al brazo de monoterapia con tremelimumab; o desde la selección hasta 180 días posteriores para los aleatorizados al brazo de terapia de combinación con MEDI4736 + tremelimumab
    19. Media del intervalo QT corregido para la frecuencia cardíaca (QTc) ? 470 ms calculada a partir de 3 electrocardiogramas (ECG) con la corrección de Fridericia.
    20. Tienen alergias conocidas o hipersensibilidad al PI o a algún excipiente del PI.
    21. Padecen alguna enfermedad que, en opinión del investigador, podría interferir en la evaluación del PI o en la interpretación de los resultados de seguridad del paciente o del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is ORR. ORR is defined as the number (%) of patients with a confirmed overall response of CR (complete response) or PR (partial response) and will be based on all treated patients who have measurable disease at baseline per ICR (evaluable set). A confirmed response of CR/PR means that a response of CR/PR 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 CR/PR 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 ORR. Any patient who discontinues treatment without progression, receives a subsequent therapy, and then responds will not be included as responders in the ORR.
    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 (grupo evaluable). 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.
    Cualquier paciente que suspenda el tratamiento sin progresión, reciba otro tratamiento y entonces presente respuesta, no será incluido como paciente que responde al tratamiento en la TRO.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The initial data cut-off will take place approximately 6 months after the last patient is first dosed. All study endpoints will be analyzed at this time with the exception of OS (overall survival). A further analysis of all study endpoints including OS will take place approximately 12 months after the last patient is dosed. A final analysis of OS and safety will be conducted approximately 18 months after the last patient is dosed.
    El corte inicial de los datos tendrá lugar aproximadamente 6 meses después de que el último paciente reciba su primera administración., momento en el que se analizarán todos los criterios de valoración del estudio excepto la SG. Unos 12 meses después de la administración de la dosis al último paciente, se analizarán todos los criterios de valoración del estudio incluida la SG y, unos 18 meses después de esta dosis, se realizará un análisis final de seguridad, SLP y SG.
    E.5.2Secondary end point(s)
    1) Duration of response (DoR) will be defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. The end of response should coincide with the date of progression or death from any cause used for the RECIST 1.1 PFS (Progression-free survival) endpoint. The denominator for DoR will be defined as described for ORR.
    2) Disease control rate (DCR) at 4 or 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR in the first 4 or 12 months, respectively, or who have demonstrated SD (Stable disease) for a minimum interval of 16 or 52 weeks, following the start of study treatment.
    3) Progression-free survival (PFS) will be defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
    4) Overall survival (OS) is defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
    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. Death dates may be found by checking publicly available death registries.
    5) Best objective response (BoR) is calculated based on the overall visit responses from each RECIST assessment. It is the best response a patient has had during their time in the study up until RECIST progression (or confirmed progression where applicable) or the last evaluable assessment in the absence of RECIST progression. CR or PR must be confirmed. BoR will be determined programmatically based on RECIST using ICR data using all data up until the first progression event. It will also be assessed using the irRC (Immune-related response criteria) data obtained from ICR.
    Duración de la respuesta. La DdR (por los RECIST 1.1 según la valoración de la RCI) se definirá como el 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. El final de la respuesta deberá coincidir con la fecha de la progresión o de la defunción por cualquier causa utilizada para calcular el criterio de valoración SLP según los criterios RECIST 1.1. El denominador de la DdR se definirá de la misma forma que ya se ha descrito para la TRO.
    Tasa de control de enfermedad. La TCE a los 4 o a los 12 meses se define como el 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 (-7 días, es decir, 105 o 357 días respectivamente) desde el inicio del tratamiento del estudio.
    Supervivencia libre de progresión. La SLP (de acuerdo con los criterios RECIST 1.1 y según la valoración de la RCI) se definirá como el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la progresión objetiva de la enfermedad o la muerte (por cualquier causa a falta de progresión), con independencia de si el paciente abandona el tratamiento o recibe otro tratamiento oncológico antes de la progresión. Los pacientes que no muestren progresión o que hayan muerto en el momento del análisis serán censurados en la fecha de evaluación más reciente desde su última valoración evaluable según los criterios RECIST 1.1.
    Supervivencia global. La SG se define como el tiempo transcurrido entre la fecha de la aleatorización y la defunción por cualquier causa. Los datos de los pacientes cuyo fallecimiento se desconozca en el momento del análisis se censurarán basándose en la última fecha registrada en la que se sabía que el paciente estaba vivo.
    Nota: las llamadas para comprobar la supervivencia se realizarán la semana siguiente a la fecha del valor de corte de los datos para el análisis y, si se confirma que los pacientes están vivos o si la fecha
    de la defunción es posterior a la fecha del valor de corte de los datos, estos pacientes serán censurados en la fecha del valor de corte de los datos. Las fechas de las defunciones se pueden obtener
    consultando los registros de defunciones, que son de consulta pública.
    Mejor respuesta objetiva. La MRO se calcula en función de las respuestas globales de las visitas de cada evaluación de los
    criterios RECIST (descritos en el Apéndice F). Se trata de 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, cuando corresponda) o la última valoración evaluable a falta de una progresión según los RECIST.
    Se clasificará la MRO en función de los RECIST (Apéndice F) usando las siguientes categorías de respuesta: RC, RP, EE, EP y NE.
    La RC o RP debe estar confirmada. La MRO se determinará programáticamente en función de los RECIST usando los datos de la RCI y todos los datos obtenidos hasta el primer acontecimiento de
    progresión. También se evaluará usando los datos de los CRi obtenidos de la RCI.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) DoR - will be defined as the latest of the dates contributing towards the first visit response of CR or PR;
    2) DCR - in the first 4 or 12 months;
    3) PFS - from the date of randomization until the date of objective disease progression or death. PFS time will always be derived based on scan/assessment dates not visit dates;
    4) OS - in the week following the date of data cut-off for the analysis;
    5) BoR - if the death occurs ?17 weeks after enrollment, then BoR will be assigned to PD category, if the death occurs >17 weeks BoR will be assigned to the NE category.
    1)DdR. El momento de la respuesta inicial se definirá como la más reciente de las fechas que hayan contribuido a la primera respuesta de RC o RP en las visitas.
    2) TCE. En los 4 o 12 meses.
    3) SLP. Desde la fecha de aleatorización hasta la fecha del objetivo de progresión de la enfermedad o muerte. El tiempo de SLP siempre se calculará a partir de las fechas de las pruebas/evaluaciones, no de las
    visitas.
    4) SG. En la semana siguiente a la fecha de corte de los datos de análisis.
    5) MRO. Si la defunción se produce ?17 semanas después de la inscripción, entonces se asignará la MRO a la categoría de progresión (EP). Si la defunción se produce > 17 semanas
    después de la fecha de inscripción, entonces 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned13
    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 en el estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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: 96
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 144
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 240
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the final analysis, AstraZeneca will continue to supply open-label drug to patients receiving the assigned IP 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.
    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 Decision2015-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-06
    P. End of Trial
    P.End of Trial StatusCompleted
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