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    Summary
    EudraCT Number:2019-002721-30
    Sponsor's Protocol Code Number:NIPU
    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:2021-06-08
    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 number2019-002721-30
    A.3Full title of the trial
    Nivolumab and ipilimumab +/- UV1 vaccination as second line treatment in patients with malignant mesothelioma (the NIPU-study)
    Nivolumab e ipilimumab +/- vacuna UV1 como segunda línea de tratamiento en pacientes con mesotelioma maligno (estudio NIPU)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nivolumab and ipilimumab +/- UV1 vaccination as second line treatment in patients with malignant mesothelioma (the NIPU-study)
    Nivolumab e ipilimumab +/- vacuna UV1 como segunda línea de tratamiento en pacientes con mesotelioma maligno (estudio NIPU)
    A.3.2Name or abbreviated title of the trial where available
    CA209-7HF NIPU
    CA209-7HF NIPU
    A.4.1Sponsor's protocol code numberNIPU
    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 SponsorOslo University Hospital
    B.1.3.4CountryNorway
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBMS Pharmaceuticals Ltd
    B.4.2CountryNorway
    B.4.1Name of organisation providing supportUltimovacs
    B.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOslo University Hospital
    B.5.2Functional name of contact pointNational Coordinating Investigator
    B.5.3 Address:
    B.5.3.1Street AddressUllernchausseen 70
    B.5.3.2Town/ cityOslo
    B.5.3.3Post code0379
    B.5.3.4CountryNorway
    B.5.4Telephone number4722934000
    B.5.5Fax number4722935808
    B.5.6E-mailahh@ous-hf.no
    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 Yervoy (ipilimumab)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 nameYervoy
    D.3.4Pharmaceutical form 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 INNIPILIMUMAB
    D.3.9.1CAS number 477202-00-9
    D.3.9.2Current sponsor codeBMS-734016
    D.3.9.3Other descriptive nameIPILIMUMAB
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 Opdivo (nivolumab)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 nameOpdivo
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form 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 INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codeBMS-936558
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 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 nameUV1
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 1331848-79-3
    D.3.9.3Other descriptive nameP719-20
    D.3.9.4EV Substance CodeSUB171636
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.450
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 1221082-45-6
    D.3.9.3Other descriptive nameP725
    D.3.9.4EV Substance CodeSUB171638
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.225
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 524061-04-9
    D.3.9.3Other descriptive nameP728
    D.3.9.4EV Substance CodeSUB171637
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.225
    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) Yes
    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: 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 Yes
    D.2.1.1.1Trade name Leukine
    D.2.1.1.2Name of the Marketing Authorisation holderPartner Therapeutics, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameLeukine
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSARGRAMOSTIM
    D.3.9.1CAS number 123774-72-1
    D.3.9.4EV Substance CodeSUB10450MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 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
    Malignant pleural mesothelioma (MPM)
    Mesotelioma pleural maligno (MPM)
    E.1.1.1Medical condition in easily understood language
    Malignant pleural mesothelioma (MPM)
    Mesotelioma pleural maligno (MPM)
    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 10059518
    E.1.2Term Pleural mesothelioma malignant
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate and compare the efficacy of nivolumab and ipilimumab with or without UV1-vaccine in patients with inoperable malignant pleural mesothelioma progressing after first-line platinum-based chemotherapy, as measured by investigator-assessed progression-free survival (PFS).
    Evaluar y comparar la eficacia del nivolumab e ipilimumab con o sin vacuna UV4 en pacientes con mesotelioma pleural maligno inoperable con progresión tras una primera línea de quimioterapia con platino, medido como supervivencia libre de progresión por el investigador.
    E.2.2Secondary objectives of the trial
    Objective response rate (ORR), disease control rate (DCR), time to response and duration of response (DOR) will be evaluated in all patients according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (Modified RECIST). To evaluate differences in Overall Survival (OS).

    To evaluate and compare patient-reported outcomes (PROs) of lung cancer symptoms, patient functioning, and health-related quality of life (HRQoL) between treatment arms as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and it's Lung Cancer Module (LC13)
    Tasa de respuesta objetiva (RO), la tasa de control de la enfermedad (TCE), el tiempo de respuesta (TR) y la duración de la respuesta (DR) será evaluado según los Criterios de Evaluación de respuesta en los Tumores Sólidos, versión 1.1 (RECIST modificados). Para evaluar diferencias en la Supervivencia Global (SG).

    Evaluar los cambios desde el inicio del tratamiento en los resultados informados por los pacientes (PRO) en los síntomas del cáncer de pulmón, el funcionamiento del paciente, y la calidad de vida relacionada con la salud (CVRS) entre los brazos de tratamiento medido con el Cuestionario de calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC) Core 30 (QLQ-C30) y puntuaciones en su Módulo del Cáncer de Pulmón (LC13).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet all of the following criteria to be eligible for study entry:
    • Histologically and/or cytologically confirmed malignant pleural mesothelioma.
    • Unresectable disease (defined as the participant not being a candidate for curative surgery).
    • Measurable disease, defined as at least 1 lesion (measurable) that can be accurately assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment (modified RECIST).
    • Available unstained archived tumor tissue sample in sufficient quantity to allow for analyses. At least fifteen unstained slides or a tumor block (preferred). NOTE: A fine needle aspiration sample is not sufficient to make the patient eligible for enrollment. Given the complexity of mesothelioma pathological diagnosis , it is expected that they will have a core needle biopsy or surgical tumor biopsy as part of their initial diagnostic work up.
    • Age ≥ 18 years.
    • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
    • Willing to provide archived tumor tissue and blood samples for research.
    • Adequate organ function as defined below
     Haemoglobin ≥9.0 g/dL
     Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3)
     Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3)
     Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
     AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
     Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
    • Previously treated with at least one line of platinum -pemetrexed
    Los pacientes deberán cumplir todos los criterios a continuación descritos para poder entrar en el estudio:
    1. Mesotelioma pleural maligno confirmado histológica y/o citológicamente.
    2. Enfermedad no operable (el paciente no se puede someter a cirugía curativa).
    3. Enfermedad medible, es decir, presencia de al menos una lesión (medible) que se pueda realizar una evaluación basal mediante tomografía computarizada (TAC) o resonancia magnética (RMN) y que pueda ser objeto de repetidas evaluaciones (RECIST modificados).
    4. Disponibilidad de una muestra de tejido tumoral archivado sin tinción en cantidad suficiente para su análisis. Disponibilidad de al menos 15 placas sin tinción o de un bloque tumoral (opción preferible). NOTA: No es suficiente con contar con una muestra de aspiración con aguja fina para que un paciente sea candidato a inclusión. Dada la complejidad del diagnóstico del mesotelioma, se espera disponer de una biopsia con aguja gruesa o de una biopsia tumoral quirúrgica como parte de los procedimientos diagnósticos iniciales.
    5. Edad ≥ 18 años.
    6. Calidad de vida de 0-1 en la escala ECOG.
    7. Voluntad de facilitar tejido tumoral de archivo y muestras de sangre para el estudio.
    8. Función orgánica adecuada, definida como:
    a. Hemoglobina ≥9,0 g/dL
    b. Recuento absoluto de neutrófilos (ANC) 1,5 (or 1.0) x (> 1500 por mm3)
    c. Recuento de plaquetas ≥100 (o 75) x 109/L (>75.000 por mm3)
    d. Bilirrubina sérica ≤1,5 x límite superior o normal institucional (ULN).
    e. AST (SGOT)/ALT (SGPT) ≤2,5 x el límite superior o normal institucional salvo que existan metástasis hepáticas, en cuyo caso deberá ser ≤5x ULN
    f. Aclaramiento de creatinina medido (CL) >40 mL/min o aclaramiento de creatinina calculado CL>40 mL/min mediante la fórmula de Cockcroft-Gault (Cockcroft and Gault 1976) o mediante la obtención de orina de 24 horas para la determinación del aclaramiento de la creatinina:
    9. Tratamiento anterior con al menos una línea de platino -pemetrexed
    E.4Principal exclusion criteria
    The subject must be excluded from participating in the trial if the subject has/is:

    • Disease suitable for curative surgery
    • Previous treatment with a PD-1 or PD-L1 inhibitor, including nivolumab or any other agent targeting immune checkpoints.
    • Non-pleural mesothelioma e.g. mesothelioma arising in peritoneum, tunica vaginalis or any serosal surface other than the pleura.
    • Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ.
    • Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids (prednisone >10 mg or equivalent). Surgery, radiation and/or corticosteroids (any dose >10 mg prednisone equivalent) must have been completed ≥ 2 weeks prior to registration.
    • Uncontrolled seizures.
    • Current or prior use of immunosuppressive medication within 28 days before the first dose of nivolumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Standard steroid premedication given prior to chemotherapy or as prophylaxis for imaging contrast allergy should not be counted for this criterion.
    • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome) within the past 2 years. Subjects with vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic treatment (within the past 3 years) are not excluded.
    • History of primary immunodeficiency.
    • History of allogeneic organ transplant.
    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
    • Active infection including tuberculosis (clinical evaluation including: physical examination findings, radiographic findings, positive PPD test, etc.), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies as defined by a positive ELISA test). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. HIV testing is not required in the absence of clinical suspicion.
    • Known history of leptomeningeal carcinomatosis.
    • Pregnant or lactating women
    • Live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving nivolumab.
    • Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results.
    El sujeto será excluido del estudio si presenta:

    1. Enfermedad susceptible de cirugía curativa.
    2. Tratamiento previo con un inhibidor de PD1 o PD-L1, incluido el nivolumab o cualquier otro agente dirigido contra puntos de control inmunitarios.
    3. Mesotelioma no pleural como el mesotelioma originado en el peritoneo, tunica vaginalis o en cualquier superficie serosa que no sea la pleura.
    4. Segunda enfermedad maligna activa que no sea el cáncer de piel no melanoma o el carcinoma cervical in situ.
    5. Metástasis cerebrales sintomáticas o incontroladas que requieres tratamiento concurrente, incluyendo, entre otros, cirugía, radiación, y/o terapia corticoesteroide (prednisona >10 mg o equivalente). Cirugía, radiación y/o corticoesteroides (cualquier dosis > 10 mg de prednisona o un equivalente) debiendo haberlo finalizado hace ≥ 2 semanas antes de su registro.
    6. Convulsiones incontroladas.
    7. Uso actual o previo de medicación inmunosupresora en los 28 días anteriores a la primera dosis de nivolumab, con la excepción de corticoesteroides intranasales o inhalados o corticoesteroides sistémicos a dosis fisiológicas, que no deberán superar los 10 mg/día de prednisona, o un corticoesteroide equivalente. No se incluyen en este criterio la premedicacion estándar con esteroides administrada previamente a la quimioterapia o como profilaxis para la alergia a agentes de contraste.
    8. Enfermedades autoinmunes o inflamatorias activas o documentadas (incluida la enfermedad inflamatoria intestinal, la diverticulitis con la excepción de diverticulosis, enfermedad celíaca, enfermedad del intestino irritable; Síndrome de Wegner) en los últimos dos años. No se excluirá a los sujetos con vitiligo, alopecia, enfermedad de Grave o psoriasis que no requieran tratamiento sistémico (en lo últimos 3 años).
    9. Historia de inmunodeficiencia primaria.
    10. Historia de trasplante alogénico de órgano
    11. Enfermedad intercurrente no controlada que incluye, entre otras, infección en curso o activa, insuficiencia cardíaca congestiva sintomática, hipertensión no controlada, angina de pecho inestable, arritmia cardíaca, enfermedad ulcerosa péptica activa o gastritis, diátesis hemorrágica activa, incluido cualquier sujeto con enfermedad psiquiátrica o situación social conocida que limitarían el cumplimiento de los requisitos del estudio o comprometerían la capacidad del sujeto para dar su consentimiento informado por escrito.
    12. Infección activa, incluida la tuberculosis (evaluación clínica que incluye: hallazgos en examen físico, hallazgos radiográficos, prueba de PPD positiva, etc.), hepatitis B (resultado positivo conocido del antígeno de superficie del VHB [HBsAg]), hepatitis C o virus de inmunodeficiencia humana (VIH positivo 1 / 2 anticuerpos definidos por una prueba ELISA positiva). Se podrá incluir a los pacientes con una infección del VHB pasada o resuelta (definida como la presencia de anticuerpos del núcleo de la hepatitis B [anti-HBc] y la ausencia de HBsAg. Solo se podrá incluir a los pacientes con anticuerpos de la hepatitis C (VHC) solo si la reacción en cadena de la polimerasa es negativa para ARN del VHC. No es necesaria la prueba del VIH en ausencia de sospecha clínica.
    13. Historia conocida de carcinomatosis leptomeníngea.
    14. Mujeres embarazadas o en periodo de lactancia
    15. Vacuna viva atenuada en los 30 días anteriores a la entrada en el estudio o en los 30 días posteriores a la toma de nivolumab.
    16. Cualquier enfermedad que, en opinión del investigador, pudiera interferir con la evaluación del tratamiento en estudio o en la interpretación de la seguridad del paciente o en los resultados del estudio.
    17. Antecedentes de alergia o hipersensibilidad a cualquiera de las sustancias activas o excipientes del fármaco del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Hypothesis: When UV1 is used in combination with nivolumab and ipilimumab, the combination does improve progression-free survival (PFS) compared with nivolumab and ipilimumab alone
    Hipótesis: Cuando se utiliza UV1 en combinación con nivolumab e ipilimumab, la combinación mejora la supervivencia libre de progresión (SLP) frente al nivolumab e ipilimumab solos.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24-month period and followed for a minimum of 2-3 months after the last patient is randomized.
    Período de 24 meses y seguido durante un mínimo de 2-3 meses después de que se aleatoriza al último paciente.
    E.5.2Secondary end point(s)
    Objective response rate (ORR), disease control rate (DCR), time to response and duration of response (DOR) will be evaluated in all patients according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (Modified RECIST). To evaluate differences in Overall Survival (OS).

    To evaluate and compare patient-reported outcomes (PROs) of lung cancer symptoms, patient functioning, and health-related quality of life (HRQoL) between treatment arms as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and it's Lung Cancer Module (LC13)
    Tasa de respuesta objetiva (RO), la tasa de control de la enfermedad (TCE), el tiempo de respuesta (TR) y la duración de la respuesta (DR) será evaluado según los Criterios de Evaluación de respuesta en los Tumores Sólidos, versión 1.1 (RECIST modificados). Para evaluar diferencias en la Supervivencia Global (SG).

    Evaluar los cambios desde el inicio del tratamiento en los resultados informados por los pacientes (PRO) en los síntomas del cáncer de pulmón, el funcionamiento del paciente, y la calidad de vida relacionada con la salud (CVRS) entre los brazos de tratamiento medido con el Cuestionario de calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC) Core 30 (QLQ-C30) y puntuaciones en su Módulo del Cáncer de Pulmón (LC13).
    E.5.2.1Timepoint(s) of evaluation of this end point
    24-month period and followed for a minimum of 2-3 months after the last patient is randomized.
    Período de 24 meses y seguido durante un mínimo de 2-3 meses después de que se aleatoriza al último paciente.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Australia
    Denmark
    Finland
    Norway
    Spain
    Sweden
    E.8.7Trial has a data monitoring committee Yes
    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
    All subjects will be followed for survival until the end of the study defined as the last expected visit of the last subject on study, approximately 5 years after the last subject initiate treatment with investigational product or when the sponsor stops the study, whichever occurs earlier.
    Todos los sujetos serán seguidos para la supervivencia hasta el final del estudio definido como la última visita esperada del último sujeto en estudio, aproximadamente 5 años después de que el último sujeto inicie el tratamiento con el producto en investigación o cuando el promotor interrumpa el estudio, lo que ocurra primero.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 59
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 59
    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 118
    F.4.2.2In the whole clinical trial 118
    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)
    The patients will be followed as expected normal treatment of the condition under investigation.
    Los pacientes serán seguidos como tratamiento normal esperado de la condición bajo investigación.
    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 Decision2021-06-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-19
    P. End of Trial
    P.End of Trial StatusOngoing
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