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    Summary
    EudraCT Number:2016-004407-31
    Sponsor's Protocol Code Number:R2810-ONC-1624
    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:2017-05-23
    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 number2016-004407-31
    A.3Full title of the trial
    A GLOBAL, RANDOMIZED, PHASE 3, OPEN-LABEL STUDY OF REGN2810 (ANTI-PD 1 ANTIBODY) VERSUS PLATINUM BASED CHEMOTHERAPY IN FIRST LINE TREATMENT OF PATIENTS WITH ADVANCED OR METASTATIC PD L1 + NON-SMALL CELL LUNG CANCER
    Estudio de Fase 3, global, aleatorizado y abierto, de REGN2810 (anticuerpo
    anti PD 1) frente a quimioterapia basada en platino como tratamiento de
    primera línea de pacientes con cáncer de pulmón no microcítico PD-L1+
    avanzado o metastásico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A STUDY OF REGN2810 (ANTI-PD 1 ANTIBODY) VERSUS STANDARD OF CARE IN PATIENTS WITH LUNG CANCER
    ESTUDIO DEL REGN2810 (ANTICUERPO ANTI PD 1) FRENTE AL
    TRATAMIENTO DE REFERENCIA EN PACIENTES CON CÁNCER DE PULMÓN
    A.4.1Sponsor's protocol code numberR2810-ONC-1624
    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 SponsorRegeneron Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportRegeneron Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRegeneron Ireland
    B.5.2Functional name of contact pointDermot Curtin
    B.5.3 Address:
    B.5.3.1Street AddressHarcourt Street, Europa House, Block 9 Harcourt Centre
    B.5.3.2Town/ cityDublin
    B.5.3.3Post code2
    B.5.3.4CountryIreland
    B.5.4Telephone number+3531411 2226
    B.5.5Fax number+3531686 4924
    B.5.6E-maildermot.curtin@regeneron.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 nameREGN2810
    D.3.2Product code REGN2810
    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 INNN/A
    D.3.9.2Current sponsor codeREGN2810
    D.3.9.3Other descriptive nameREGN2810
    D.3.9.4EV Substance CodeSUB179369
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number350
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Carboplatin 10 mg/ml concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Concentrate for 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 INNCarboplatin
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    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 RoleComparator
    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 Cisplatin 1 mg/ml Concentrate for Solution for Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Concentrate for 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 INNCisplatin
    D.3.9.3Other descriptive nameCISPLATIN
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Gemcitabine 2 g Powder for Solution for Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Powder for 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 INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Paclitaxel 6 mg/ml Concentrate for Solution for Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Concentrate for 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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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: 6
    D.1.2 and D.1.3IMP RoleComparator
    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 Armisarte 25 mg/ml concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC ehf.
    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.3.4Pharmaceutical form Concentrate for 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 INNPEMETREXED
    D.3.9.1CAS number 137281-23-3
    D.3.9.4EV Substance CodeSUB09655MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-Small Cell Lung Cancer
    Cancer de Pulmón metastasico o avanzado
    E.1.1.1Medical condition in easily understood language
    Lung Cancer
    Cancer de Pulmón
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to compare the progression-free survival (PFS) of REGN2810 versus standard-of-care platinum-based chemotherapies in the first-line treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed cell death ligand-1 (PD-L1) in ≥50% of tumor cells.
    El objetivo principal del estudio es comparar las supervivencias sin progresión (SSP) obtenidas con el REGN2810 y con las quimioterapias con platino utilizadas habitualmente en el tratamiento de primera línea de los pacientes con carcinoma pulmonar no microcítico (CPNM) avanzado o metastásico cuyos tumores expresan el ligando de muerte celular programada (PD-L1) en ≥ 50 % de las células tumorales.
    E.2.2Secondary objectives of the trial
    The key secondary objectives of the study are to compare REGN2810 versus platinum based chemotherapies with respect to the following:
    • Overall survival (OS)
    • Objective response rates (ORR)
    Los objetivos secundarios clave del estudio son comparar el REGN2810 con las quimioterapias con platino en relación con lo siguiente:
    • Supervivencia global (SG)
    • Tasas de respuesta objetiva (TRO)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional Genomics Sub-study.
    The purpose of the genomic analyses is to identify genomic associations with clinical or biomarker response, other clinical outcome measures, and possible AEs.
    Subestudio de genómica opcional.
    La finalidad de los análisis genómicos es identificar asociaciones genómicas con la respuesta clínica o de biomarcadores, otros criterios de valoración clínica y posibles AA.
    E.3Principal inclusion criteria
    1.Men and women ≥18 years of age (≥20 years of age in Japan)
    2.Patients with histologically or cytologically documented squamous or non squamous NSCLC with stage IIIB or stage IV disease who received no prior systemic treatment for recurrent or metastatic NSCLC
    a.Patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation therapy) and developed recurrent or metastatic disease more than 6 months after completing therapy are eligible
    3.Archival or newly obtained formalin-fixed tumor tissue from a metastatic/recurrent site, which has not previously been irradiated
    4.Tumor cells expressing PD L1 in ≥50% of tumor cells by IHC performed by the central laboratory
    5.At least 1 radiographically measureable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria (see Appendix 4). Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site.
    6.ECOG performance status of ≤1
    7.Anticipated life expectancy of at least 3 months
    8.Adequate organ and bone marrow function as defined below:
    a.Hemoglobin ≥9.0 g/dL
    b.Absolute neutrophil count ≥1.5 × 109/L
    c.Platelet count ≥100,000/mm3
    d.Glomerular filtration rate (GFR) >30 mL/min/1.73m2
    e.Total bilirubin ≤1.5 × upper limit of normal (ULN) (if liver metastases ≤3 × ULN), with the exception of patients diagnosed with clinically confirmed Gilbert’s syndrome
    f.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN or ≤5 × ULN, if liver metastases
    g.Alkaline phosphatase ≤2.5 × ULN (or ≤5.0 × ULN, if liver or bone metastases)
    h.Not meeting criteria for Hy’s law (ALT >3 × ULN and bilirubin >2 × ULN)
    9.Willing and able to comply with clinic visits and study-related procedures
    10.Provide signed informed consent
    11.Able to understand and complete study-related questionnaires
    1. Hombres y mujeres ≥ 18 años de edad (≥ 20 años de edad en Japón).
    2. Pacientes con CPNM epidermoide o no epidermoide en fase IIIB o IV, documentado histológica o citológicamente, que no hayan recibido anteriormente ningún tratamiento sistémico para el CPNM recurrente o mestastásico.
    a. Se considerarán aptos para participar los pacientes que hayan recibido biquimioterapia con platino antes o después de la cirugía o radioterapia, y que hayan presentado enfermedad recurrente o metastásica más de 6 meses después de finalizar el tratamiento.
    3. Tejido tumoral fijado en formol de archivo o recién obtenido de un foco metastásico/recurrente no irradiado con anterioridad.
    4. Expresión de PD L1 en ≥ 50 % de las células tumorales determinada mediante IHQ realizada por el laboratorio central.
    5. Al menos 1 lesión radiológicamente mensurable mediante tomografía computerizada (TC) o resonancia magnética (RM) con arreglo a los criterios RECIST 1.1 (véase el anexo 4). Las lesiones analizadas pueden estar situadas en un campo previamente irradiado si existe progresión de la enfermedad documentada (radiográficamente) en dicho lugar.
    6. Estado funcional del ECOG ≤ 1.
    7. Esperanza de vida prevista de 3 meses como mínimo.
    8. Funcionamiento satisfactorio de los órganos y la médula ósea, según la definición siguiente:
    a. Hemoglobina ≥ 9,0 g/dl
    b. Cifra absoluta de neutrófilos ≥ 1,5 × 109/l
    c. Cifra de plaquetas ≥ 100 000/mm3
    d. Filtración glomerular (FG) > 30 ml/min/1,73 m2
    e. Bilirrubina total ≤ 1,5 veces el límite superior de la normalidad (LSN) (si existen metástasis hepáticas ≤ 3 veces el LSN), excepto los pacientes con diagnóstico de síndrome de Gilbert clínicamente confirmado
    f. Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ≤ 3 veces el LSN o ≤ 5 veces el LSN si existen metástasis hepáticas
    g. Fosfatasa alcalina ≤ 2,5 veces el LSN (o ≤ 5,0 veces el LSN si existen metástasis óseas o hepáticas)
    h. Incumplimiento de los criterios de la ley de Hy (ALT > 3 veces el LSN y bilirrubina > 2 veces el LSN)
    9. Deseo y capacidad de realizar las visitas al centro y someterse a los procedimientos relacionados con el estudio.
    10. Otorgamiento del consentimiento informado.
    11. Capacidad para comprender y cumplimentar los cuestionarios relacionados con el estudio.
    E.4Principal exclusion criteria
    1.Patients that have never smoked, defined as smoking ≤100 cigarettes in a lifetime
    2.Active or untreated brain metastases or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases are adequately treated and patients have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. Patients must be off (immunosuppressive doses of) corticosteroid therapy.
    3.Patients with tumors tested positive for EGFR gene mutations, ALK gene translocations, or ROS1 fusions
    4.Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
    5.History of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management. A history of radiation pneumonitis in the radiation field is permitted.
    6.Patients with active, known, or suspected autoimmune disease that has required systemic therapy in the past 2 years. Patients with vitiligo, type I diabetes mellitus, and hypothyroidism (including hypothyroidism due to autoimmune thyroiditis) only requiring hormone replacement are permitted to enroll.
    7.Patients with a condition requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) within 14 days of randomization. Physiologic replacement doses are allowed even if they are >10 mg of prednisone/day or equivalent, as long as they are not being administered for immunosuppressive intent. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder.
    8.Another malignancy that is progressing or requires treatment, with the exception of nonmelanomatous skin cancer that has undergone potentially curative therapy, or in situ cervical carcinoma or any other tumor that has been treated, and the patient is deemed to be in complete remission for at least 2 years prior to study entry, and no additional therapy is required during the study period.
    9.Known active hepatitis B (positive result) or hepatitis C (known positive result) and known quantitative HCV RNA results greater than the lower limits of detection of the assay)
    10.Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome indicating uncontrolled active infection. Patients on highly active antiretroviral therapy with undetectable RNA levels and CD4 counts above 350 are permitted.
    11.Active infection requiring systemic therapy within 14 days prior to randomization
    12.Prior therapy with anti-PD 1 or anti-PD L1. Prior exposure to other immunomodulatory or vaccine therapy such as anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies is permitted, but the last dose of such an antibody should have been at least 3 months prior to the first dose of study drug.
    13.Treatment-related immune-mediated AEs from immune-modulatory agents (including but not limited to anti-PD1/PD-L1 Mabs, anti-CTLA4 monoclonal antibodies, and PI3K δ inhibitors) that have not resolved to baseline at least 3 months prior to initiation of treatment with study therapy. Patients are excluded from treatment with REGN2810 if they experienced immune-mediated AEs related to prior treatment with a blocker of the PD-1/PD-L1 pathway that were grade 3 or 4 in severity and/or required discontinuation of the agent, regardless of time of occurrence.
    14.Receipt of an investigational drug or device within 30 days of screening or within 5 half lives of the investigational drug or therapy being studied (whichever is longer)
    15.Receipt of a live vaccine within 30 days of planned start of study medication
    16.Major surgery or significant traumatic injury within 4 weeks prior to first dose
    17.Documented allergic or acute hypersensitivity reaction attributed to antibody treatments
    18.Known allergy to doxycycline or other tetracycline antibiotics
    19.Known psychiatric or substance abuse disorder that would interfere with participation with the requirements of the study, including current use of any illicit drugs
    20.Pregnant or breastfeeding women.
    1. No haber fumado nunca (≤ 100 cigarrillos en toda la vida).
    2. Metástasis cerebrales activas o sin tratar o compresión de la médula espinal. Se considerarán aptos si se han tratado satisfactoriamente las metástasis en el sistema nervioso central y los pacientes han recuperado los valores basales desde el punto de vista neurológico (a excepción de los signos o síntomas residuales relacionados con el tratamiento del SNC) durante
    al menos las 2 semanas anteriores a la inclusión. Los pacientes no deben estar recibiendo tratamiento con (dosis inmunodepresoras de) corticoesteroides.
    3. Pacientes con tumores con mutaciones del gen EGFR, translocación del gen ALK o fusiones de ROS1.
    4. Encefalitis, meningitis, convulsiones sin controlar durante el año anterior a la firma del consentimiento informado.
    5. Antecedentes de enfermedad pulmonar intersticial (p. ej., fibrosis pulmonar idiopática, neumonía organizada) neumonitis no infecciosa activa, cuyo tratamiento haya necesitado dosis inmunodepresoras de glucocorticoides. Están permitidos antecedentes de neumonitis por radioterapia en el campo irradiado.
    6. Pacientes con enfermedad autoinmunitaria activa, comprobada o sospechada para la que haya sido necesario un tratamiento sistémico en los 2 últimos años. Está permitida la inclusión de pacientes con vitíligo, diabetes mellitus de tipo 1 e hipotiroidismo (incluido el hipotiroidismo secundario a una tiroiditis autoinmunitaria) que solo necesiten reposición hormonal.
    7. Pacientes con dolencias que precisen tratamiento con corticoesteroides (> 10 mg de prednisona/día) en los 14 días siguientes a la aleatorización. Están permitidas las dosis fisiológicas de reposición siempre que no se administren con finalidad inmunodepresora, aunque sean > 10 mg de prednisona/día. Están permitidos los corticoides inhalados o tópicos siempre que no se administren para tratar trastorno autoinmunitario.
    8. Otra neoplasia maligna que esté empeorando o requiera tratamiento, excepto el cáncer de piel no melánico para el que se haya administrado un tratamiento potencialmente curativo o el carcinoma cervicouterino localizado o cualquier otro tumor que haya sido tratado y se considere que el paciente presenta remisión completa durante al menos los 2 años anteriores a la incorporación al estudio y no se necesite tratamiento adicional durante el periodo de estudio.
    9. Hepatitis B activa comprobada (result positivo) o hepatitis C (result positivo comprobado) y resultados confirmados en el análisis cuantitativo del ARN del VHC superiores a los límites inferiores de detección de la prueba
    10. Antecedentes comprobados del virus de la inmunodeficiencia humana (VIH) o síndrome de inmunodeficiencia adquirida comprobado que indique existencia de infección activa sin controlar. Se permite la inclusión de pacientes en tratamiento con antirretrovíricos de gran actividad con niveles de ARN indetectables y cifra de CD4 superior a 350.
    11. Infección activa que necesite tratamiento sistémico en los 14 días anteriores a la aleatorización.
    12. Tratamiento previo con anticuerpos anti PD 1 o anti PD L1. Está permitida la exposición previa a un tratamiento inmunomodulador o con vacunas terapéuticas, como el anticuerpo contra el antígeno 4 asociado a los linfocitos T citotóxicos (CTLA 4), siempre que la última dosis de dichos anticuerpos se haya administrado al menos 3 meses antes de la primera dosis del fármaco del estudio.
    13. AA de origen inmunitario relacionados con el tratamiento con inmunomoduladores (incluidos, entre otros, los AcM anti PD1/PD L1, los AcM anti CTLA4 y los inhibidores de PI3K δ) que no se hayan resuelto hasta volver a los valores basales al menos 3 meses antes del inicio de la administración del tratamiento del
    estudio. No se administrará el tratamiento con REGN2810 a los pacientes que hayan presentado AA de origen inmunitario relacionados con un tratamiento anterior con un inhibidor de la vía PD 1/PD L1, que hayan tenido una gravedad de grado 3 o 4 o hayan requerido la interrupción del fármaco, con independencia del momento de su
    aparición.
    14. Recepción de un fármaco o dispositivo en investigación en un plazo máximo de 30 días a partir de la selección o de 5 semividas del fármaco o tratamiento en investigación que se está estudiando (el que sea mayor).
    15. Recepción de una vacuna con microbios vivos en un plazo máximo de 30 días a partir del inicio previsto de la administración del fármaco del estudio.
    16. Cirugía mayor o lesión traumática significativa en las 4 semanas anteriores a la primera dosis.
    17. Reacción alérgica o de hipersensibilidad aguda documentada, atribuida a tratamientos con antibióticos.
    18. Alergia comprobada a la doxiciclina o a otros antibióticos tetraciclínicos.
    19. Trastorno psiquiátrico o toxicomanía comprobados que interferirían con la participación y con los requisitos del estudio, incluido el consumo actual de drogas.
    20. Mujeres embarazadas o en periodo de lactancia.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS as assessed by a blinded IRC using RECIST 1.1 (Eisenhauer 2009; see Appendix 4). Progression-free survival will be defined as the time from randomization to the date of the first documented tumor progression, as determined by the IRC (using RECIST 1.1) or death due to any cause. Patients will be censored according to rules listed below:
    1. Patients who do not have a documented tumor progression or death will be censored on the date of their last evaluable tumor assessment.
    2. Patients who do not have a documented tumor progression or death before initiation of new anti-tumor therapy will be censored on the date of their last evaluable tumor assessment prior to or on the date of new anti-tumor therapy.
    3. Patients who withdraw consent before taking any study treatment, and as a consequence have no post-baseline tumor assessment, will be censored at the date of randomization.
    4. Patients who do not have any evaluable tumor assessments after randomization and do not die will be censored on the date of randomization.
    El criterio principal de valoración es la SSP evaluada por un CRI desconocedor del tratamiento de conformidad con los criterios RECIST 1.1 (Eisenhauer 2009; véase el anexo 4). La supervivencia sin progresión (SSP) se definirá como el tiempo transcurrido entre la aleatorización y la fecha de la primera progresión del tumor documentada, determinada por el CRI (según los criterios RECIST
    1.1) o la muerte por cualquier causa. Los pacientes serán objeto de censura estadística conforme a las siguientes reglas:
    1. Los pacientes sin progresión del tumor documentada ni muerte se censurarán en la fecha del último examen del tumor evaluable.
    2. Los pacientes sin progresión del tumor documentada ni muerte antes del inicio de un nuevo tratamiento antitumoral se censurarán en la fecha del último examen del tumor evaluable antes de la fecha o en la fecha del nuevo tratamiento antitumoral.
    3. Los pacientes que retiren su consentimiento antes de tomar ningún tratamiento del estudio y que, por tanto, no se hayan sometido a ningún examen del tumor antes de la visita basal, se censurarán en la fecha de la aleatorización.
    4. Los pacientes sin exámenes del tumor evaluable tras la aleatorización y que no fallezcan se censurarán en la fecha de la aleatorización.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Through 108 weeks of treatment
    Alrededor de 108 semanas de tratamiento
    E.5.2Secondary end point(s)
    The key secondary endpoints in the study will be OS and ORR.
    Overall survival will be defined as the time from randomization to the date of death. A patient who has not died will be censored at the last known date of contact.
    Objective response rate will be defined as the number of patients with a best overall response (BOR) of confirmed CR or PR divided by the number of patients in the efficacy analysis set.
    Best overall response will be defined as the best overall response, as determined by the IRC per RECIST 1.1, between the date of randomization and the date of the first objectively documented progression or the date of subsequent anti-cancer therapy, whichever comes first.
    Los criterios secundarios de valoración en el estudio serán la SG y la TRO.
    La supervivencia global se definirá como el tiempo transcurrido entre la fecha de la aleatorización y la fecha de la muerte. Los pacientes que no hayan fallecido se censurarán en la última fecha de contacto conocida.
    La tasa de respuesta objetiva se definirá como el número de pacientes con la mejor respuesta global (MRG) de RC o RP dividido por el número de pacientes del grupo de análisis de la eficacia.
    La mejor respuesta global se definirá como la mejor respuesta global, determinada por el CRI de acuerdo con los criterios RECIST 1.1, entre la fecha de la aleatorización y la fecha de la primera progresión
    documentada objetivamente o la fecha del tratamiento antineoplásico posterior, lo que ocurra en primer lugar.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Through 108 weeks of treatment
    Alrededor de 108 semanas de tratamiento
    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 No
    E.6.11Pharmacogenomic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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 trial4
    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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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
    Argentina
    Australia
    Belarus
    Brazil
    Bulgaria
    Chile
    China
    Czech Republic
    Georgia
    Greece
    Hungary
    Italy
    Malaysia
    Philippines
    Poland
    Portugal
    Romania
    Russian Federation
    Spain
    Taiwan
    Thailand
    Turkey
    Ukraine
    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
    LVLS
    Ultima visita del ultimo participante
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months4
    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: 210
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 300
    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)
    None
    No
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-20
    P. End of Trial
    P.End of Trial StatusCompleted
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