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    Summary
    EudraCT Number:2017-003182-94
    Sponsor's Protocol Code Number:BP40234
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2017-11-22
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-003182-94
    A.3Full title of the trial
    AN OPEN-LABEL, MULTICENTER, PHASE II STUDY TO EVALUATE THE THERAPEUTIC ACTIVITY OF RO6874281, AN IMMUNOCYTOKINE, CONSISTING OF INTERLEUKIN-2 VARIANT (IL-2V) TARGETING FIBROBLAST ACTIVATION PROTEIN-Α (FAP), IN COMBINATION WITH ATEZOLIZUMAB (ANTI-PD-L1), ADMINISTERED INTRAVENOUSLY, IN PARTICIPANTS WITH ADVANCED AND/OR METASTATIC SOLID TUMORS
    ESTUDIO DE FASE II MULTICÉNTRICO, ABIERTO PARA EVALUAR LA ACTIVIDAD TERAPÉUTICA DE RO6874281, UNA INMUNOCITOQUINA COMPUESTA POR UNA VARIANTE DE INTERLEUQUINA 2 (IL-2V) DIRIGIDA CONTRA LA PROTEÍNA A DE ACTIVACIÓN DE FIBROBLASTOS (FAP), EN COMBINACION CON ATEZOLIZUMAB (ANTI-PD-L1), ADMINISTRADOS POR VÍA INTRAVENOSA, EN PACIENTES CON TUMORES SÓLIDOS AVANZADOS Y/O METASTÁSICOS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase II Study to Evaluate the Theraputic Activity of RO6874281, an Immunocytokine, Consisting of Interleukin-2 Variant (IL-2V) Targeting Fibroblast Activation Protein-Α (FAP), in Combination with Atezolizumab (Anti-PD-L1), Administered Intravenously, in Participants with Advanced and/or Metastatic Solid Tumors
    Estudio Fase II para evaluar la actividad terapéutica de RO6874281, una inmunocitoquina compuesta por una variante de interleuquina-2 (IL-2V) dirigida contra la proteína A de activación de fibroblastos (FAP) en combinación con Atezolizumab (Anti-PD-L1), administrado por via intravenosa en participantes con tumores solidos avanzados y/o metastásicos.
    A.4.1Sponsor's protocol code numberBP40234
    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 SponsorRoche Farma S.A (Soc Unipersonal) que realiza el ensayo en España y actua como representante de F Hoffmann-La Roche LTD
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+34913257300
    B.5.6E-mailspain.start_up_unit@roche.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 nameFAP-IL2 active
    D.3.2Product code RO6874281/F01
    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 codeRO6874281/F01
    D.3.9.3Other descriptive nameRO6874281; FAP-IL2v active
    D.3.9.4EV Substance CodeSUB178391
    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 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 nameFAP-IL2v diluent
    D.3.2Product code RO6874281/F02
    D.3.4Pharmaceutical form Solvent 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 INNN/A
    D.3.9.2Current sponsor codeRO6874281/F02
    D.3.9.3Other descriptive nameRO6874281; FAP-IL2v diluent
    D.3.9.4EV Substance CodeSUB178391
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0
    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 Yes
    D.3.11.13.1Other medicinal product typePR2 is the Sponsor's diluent to be used to dilute PR1. It has the same composition as PR1 drug product but does not contain the active substance.
    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 nameAtezolizumab
    D.3.2Product code RO5541267/F03
    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 INNATEZOLIZUMAB
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameMPDL3280A
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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
    Advanced and/or Metastatic Solid Tumors
    Tumores solidos avanzados y/o metastásicos
    E.1.1.1Medical condition in easily understood language
    A solid tumor/cancer is an abnormal tissue mass that arises from uncontrolled growth of cells and continues to grow locally or spread to other parts of the body (metastatic)
    Un tumor sólido / cáncer es una masa de tejido anormal que aparece de un crecimiento incontrolado de células y que continua creciendo localmente o se extiende a otras partes del cuerpo (metastasico)
    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 LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate antitumor activity of RO6874281 in combination with atezolizumab and potentially other drugs in comparison with the standard of care (SoC) in participants with advanced/and or metastatic solid tumors
    Evaluar la actividad antitumoral de RO6874281 en combinación con atezolizumab y potencialmente con otros fármacos, comparado con el TE, en pacientes con tumores sólidos avanzados y/o metastásicos.
    E.2.2Secondary objectives of the trial
    • To further characterize the antitumor activity of RO6874281 in combination with atezolizumab and potentially other drugs in participants with advanced/and or metastatic solid tumors relative to SoC
    • To evaluate the safety and tolerability of RO6874281 in combination with atezolizumab and potentially other drugs
    • To determine the relevance of the baseline tumor Programmed death-ligand 1(PD-L1) status for treatment benefit
    • To characterize in tumor samples treatment-induced pharmacodynamic effects of RO6874281 in combination with atezolizumab and potentially other drugs
    • Definir de forma más completa la actividad antitumoral de RO6874281 en combinación con atezolizumab y potencialmente con otros fármacos, en pacientes con tumores sólidos avanzados y/o metastásicos, en relación con el TE.
    • Evaluar la seguridad y la tolerabilidad de RO6874281 en combinación con atezolizumab y potencialmente con otros fármacos.
    • Determinar la relevancia del estado basal de PD-L1 en el tumor para el beneficio del tratamiento.
    • Definir en muestras de tumor los efectos FD, inducidos por el tratamiento, de RO6874281 en combinación con atezolizumab y potencialmente con otros fármacos.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age >= 18 years
    - Participants who have progressed on at least one previous regimen of anticancer therapy
    - Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
    - Eastern Cooperative Oncology Group Performance Status 0 or 1 or Karnofsky Performance Score >= 70
    - Life expectancy of >= 12 weeks
    - Confirmed at least one tumor lesion with location accessible to safely biopsy per clinical judgment of the treating physician
    - Consent to provide an archival tumor tissue sample
    - Willingness to undergo baseline and on-treatment tumor biopsies for pharmacodynamic biomarker analysis
    - Adequate cardiovascular, hematological, liver and renal function
    - Adverse events related to any previous radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade <= 1, except alopecia and Grade 2 peripheral neuropathy
    - Participants with unilateral pleural effusion are eligible if they fulfill both of the following:
    a) New York Heart Association Class 1
    b) Global initiative for obstructive lung disease test level 1
    - For male and female participants: The contraception and abstinence requirements are intended to prevent exposure of an embryo to the study treatment
    - Participants with Gilbert’s syndrome will be eligible for the study. The diagnosis of Gilbert's syndrome is suspected in people who have persistent, slightly elevated levels of unconjugated bilirubin (<=3.0 × ULN) without any other apparent cause. A diagnosis of Gilbert’s syndrome will be based on the exclusion of other diseases on the basis of the following criteria:
    a) Unconjugated hyperbilirubinemia noted on several occasions
    b) No evidence of hemolysis and lactate dehydrogenase
    c) Normal liver function tests
    d) Absence of other diseases associated with unconjugated hyperbilirubinemia
    -Tener >=18 años de edad.
    -Haber manifestado progresión de la enfermedad durante al menos un régimen de tratamiento antineoplásico previo
    -Presentar enfermedad medible, definida de acuerdo con los criterios RECIST v1.1.
    -Estado funcional ECOG 0 o 1 o puntuación >= 70 en la escala del estado funcional de Karnofsky.
    -Esperanza de vida >= 12 semanas.
    -Presentar al menos una lesión tumoral confirmada en una localización a la que se pueda acceder con seguridad para realizar una biopsia, de acuerdo con el criterio clínico del médico responsable del tratamiento
    -Otorgar el consentimiento para proporcionar una muestra de tejido tumoral conservado
    -Estar dispuestos a someterse a las biopsias tumorales realizadas en el período basal y durante el tratamiento, para el análisis farmacodinámico de biomarcadores
    -Función cardiovascular, hematológica, hepática y renal adecuada
    -Los acontecimientos adversos relacionados con cualquier tratamiento con radioterapia, quimioterapia o procedimiento quirúrgico previo deben haber remitido a grado <=1, exceptuando la alopecia (de cualquier grado) y la neuropatía periférica de grado 2.
    -Los pacientes con derrame pleural unilateral son elegiblessi se cumplen los dos criterios siguientes:
    a. Clase 1 de la NYHA.
    b. Nivel 1 en el test de la Global Initiative for Obstructive Lung Disease
    -Varones y mujeres participantes
    Los requisitos relativos a las medidas anticonceptivas y la abstinencia sexual están destinados a impedir la exposición del embrión al tratamiento del estudio.
    -Los pacientes con síndrome de Gilbert serán elegibles para el estudio. La presencia de síndrome de Gilbert se sospecha cuando un paciente presenta concentraciones ligeramente elevadas persistentes de bilirrubina no conjugada (<=3.0 x LSN) sin otra causa aparente. Para establecer el diagnóstico del síndrome de Gilbert se descartará la existencia de otras enfermedades, basándose en los criterios siguientes:
    a. Hiperbilirrubinemia no conjugada observada en varias ocasiones.
    b. Sin evidencia de hemólisis y lactato deshidrogenasa
    c. Pruebas de función hepática normales.
    d. Ausencia de otras enfermedades asociadas con hiperbilirrubinemia no conjugada.
    E.4Principal exclusion criteria
    - Symptomatic or untreated central nervous system (CNS) metastases
    - History of treated asymptomatic CNS metastases
    - Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >= 2 weeks before enrollment
    - Leptomeningeal disease
    - An active second malignancy
    - Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders, and known autoimmune diseases or other disease with ongoing fibrosis
    - Episode of significant cardiovascular/cerebrovascular acute disease within 6 months before study treatment administration, including any of the following: hypertensive crisis/encephalopathy, uncontrolled hypertension, unstable angina, transient ischemic attack/stroke, congestive heart failure of any New York Heart Association classification, serious cardiac arrhythmia requiring treatment, history of thromboembolic events, hypertensive encephalopathy
    - History of significant vascular disease
    - Peripheral arterial thrombosis within 6 months before study treatment administration
    - Active or uncontrolled infections
    - Human immunodeficiency virus or hepatitis B, or hepatitis C virus infection
    - Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 4 weeks before study treatment administration
    - History of chronic liver disease or evidence of hepatic cirrhosis
    - Serious, non-healing wound; active ulcer; or untreated bone fracture
    - Dementia or altered mental status that would prohibit informed consent
    - History of, active or suspicion of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
    - Participants with a history of autoimmune hypothyroidism on a stable dosage of thyroid replacement hormone may be eligible with approval by the Medical Monitor
    - Participants with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study with approval by the Medical Monitor
    - History of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography scan. History of radiation pneumonitis in the radiation field is permitted
    - Bilateral pleural effusion confirmed by x-ray
    - Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding that give reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug
    - Concurrent therapy with any other investigational drug
    - Immunomodulating agents
    - Chronic use of steroids
    - Radiotherapy within the last 4 weeks before start of study treatment administration, with the exception of limited field palliative radiotherapy.
    - Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1 or at any time during the study and 5 months after the last dose of atezolizumab
    - Major surgery or significant traumatic injury < 28 days before study treatment administration or anticipation of the need for major surgery during study treatment
    - Known hypersensitivity to any of the components of the RO6874281 drug product or atezolizumab drug product, including but not limited to hypersensitivity to Chinese Hamster Ovary cell products or other recombinant human or humanized antibodies
    - Severe dyspnea at rest or requiring supplementary oxygen therapy
    - Participants who require blood transfusion before and after the start of the study treatment
    -Metástasis del sistema nervioso central (SNC) sintomáticas o no tratadas.
    -Antecedentes de metástasis del SNC asintomáticas tratadas
    -Compresión de médula espinal no tratada definitivamente con cirugía y/o radioterapia o diagnosticada y tratada previamente sin evidencia de estabilización clínica de la enfermedad durante las >= 2 semanas previas a la inclusión en el estudio.
    -Enfermedad leptomeníngea
    -Pacientes con una segunda neoplasia activa
    -Evidencia de enfermedades concomitantes significativas no controladas que pudieran afectar al cumplimiento con el protocolo o a la interpretación de los resultados, incluyendo diabetes mellitus, antecedentes de trastornos pulmonares importantes y enfermedades autoinmunes confirmadas u otras enfermedades que cursan con fibrosis progresiva
    -Episodios de enfermedades cardiovasculares o cerebrovasculares agudas significativas en los 6 meses previos a la administración del tratamiento del estudio, incluyendo cualquiera de las siguientes: crisis/encefalopatía hipertensiva, hipertensión no controlada, angina de pecho inestable, ataque isquémico transitorio/ictus, insuficiencia cardíaca congestiva de cualquier clase de la NYHA, arritmias cardíacas graves que requieran tratamiento, antecedentes de acontecimientos tromboembólicos encefalopatía hipertensiva.
    -Antecedentes de enfermedad vascular significativa
    -Trombosis arterial periférica en los 6 meses previos a la administración del tratamiento del estudio.
    -Infecciones activas o no controladas
    -Infección por virus de inmunodeficiencia humana o de hepatitis B o C.
    -Infecciones activas confirmadas de etiología bacteriana, viral, micótica, micobacteriana, parasitaria u otras (exceptuando micosis de lechos ungueales) o cualquier episodio importante de infección que haya requerido tratamiento con antibióticos intravenosos u hospitalización en las 4 semanas previas a la administración del tratamiento del estudio.
    -Antecedentes de enfermedad hepática crónica o evidencia de cirrosis hepática.
    -Heridas graves no cicatrizadas, úlceras activas o fracturas óseas no tratadas.
    -Demencia o estado mental alterado que impediría otorgar el consentimiento informado.
    -Enfermedades autoinmunes en el pasado, activas o presuntivas, incluyendo aunque no exclusivamente, lupus eritematoso sistémico, artritis reumatoide, enfermedad inflamatoria intestinal, trombosis vascular asociada con síndrome antifosfolípido, granulomatosis de Wegener, síndrome de Sjögren, parálisis de Bell, síndrome de Guillain-Barré, esclerosis múltiple, vasculitis o glomerulonefritis.
    -Los pacientes con antecedentes de hipotiroidismo autoinmune que estén recibiendo dosis estables de terapia de reemplazo de la hormona tiroidea podrán ser elegibles para el estudio, si lo autoriza el monitor médico.
    -Los pacientes con diabetes mellitus tipo 1 controlada que estén recibiendo una pauta estable de insulina podrán ser elegibles para este estudio, si lo autoriza el monitor médico.
    -Antecedentes de fibrosis pulmonar idiopática, neumonitis, neumonía organizada o evidencia de neumonitis activa en la tomografía axial computarizada (TAC) de tórax realizada en el período de selección. Está permitida la inclusión de pacientes con antecedentes de neumonitis inducida por radiación en el campo irradiado.
    -Derrame pleural bilateral confirmado en radiografía.
    -Cualquier otra enfermedad, trastorno metabólico, hallazgo de la exploración física o de las pruebas de laboratorio clínico que proporcionen indicios razonables para sospechar la presencia de una enfermedad o trastorno para los cuales estaría contraindicado el uso de un fármaco en investigación.
    -Tratamiento concomitante con cualquier otro fármaco en investigación
    -Agentes inmunomoduladores
    -Uso crónico de esteroides
    -Administración de radioterapia en las 4 semanas previas al inicio del tratamiento del estudio, exceptuando radioterapia de campo limitado con intención paliativa.
    -Administración de vacunas vivas atenuadas en las 4 semanas previas al día 1 del ciclo 1 o en cualquier momento durante el estudio y 5 meses después de administrar la última dosis de atezolizumab.
    -Pacientes sometidos a un procedimiento de cirugía mayor o que han sufrido traumatismos significativos<28 días antes de administrar el tratamiento del estudio o que previsiblemente requieran una intervención de cirugía mayor durante el tratamiento del estudio.
    -Hipersensibilidad conocida a cualquiera de los componentes de los fármacos RO6874281 o atezolizumab, incluyendo, aunque no exclusivamente, hipersensibilidad a productos elaborados con células de ovario de hámster chino o a otros anticuerpos recombinantes humanos o humanizados.
    -Disnea severa en reposo o que requiera oxigenoterapia suplementaria.
    -La elegibilidad de los pacientes que requieran transfusión de sangre antes y después de iniciar el tratamiento del estudio
    E.5 End points
    E.5.1Primary end point(s)
    1) Objective response rate according to RECIST v1.1
    1) Indice de respuesta objetiva de acuerdo con los criterios RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) Approximately up to 120 days after the last dose of atezolizumab
    1) Aproximadamente hasta un máximo de 120 días después de la ultima dosis de Atezolizumab
    E.5.2Secondary end point(s)
    1) Disease control rate
    2) Duration of response
    3) Progression-free survival
    4) Overall survival
    5) Incidence of and severity of adverse event
    6) Changes in vital signs, physical findings, ECG parameters, and clinical laboratory results
    7) PD-L1 status by immunohistochemical methods
    8) Change from baseline in density (cell/mm2) of CD8+ and CD3-perforin+ cells, and PD-L1 by immunohistochemical methods
    1) Indice de control de la enfermedad
    2) Duración de la respuesta
    3) Supervivencia libre de progresion
    4) Supervivencia global
    5) Incidencia y severidad de los Acontecimientos Adversos
    6) Cambios en las constantes vitales, los hallazgos de la exploración física, parámetros del ECG y los resultados de laboratorio clínico
    7) Estado de PD-L1 determinado mediante técnicas de inmunohistoquímica
    8) Cambio respecto al valor basal de la densidad (células/mm2) de células CD8+ y CD3-perforina+ y de PD-L1, determinado mediante técnicas de inmunohistoquímica
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) to 8) Approximately up to 120 days after the last dose of atezolizumab
    1) a 8) Aproximadamente hasta un máximo de 120 después de la ultima dosis de atezolizumab
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Belgium
    Hong Kong
    Italy
    Korea, Republic of
    New Zealand
    Poland
    Singapore
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the last participant’s last visit (LPLV) per protocol (includes the follow-up visits at 28 days and 3 months after the last dose of any study drug, and 120 days after the last dose of atezolizumab, whichever occurs last) or the date at which the last data point from the last participant required for statistical analysis is received (Last Participant, Last Observation), whichever is the latest date, unless the participant was prematurely discontinued
    La terminación del estudio se define como la fecha de la última visita del último paciente segun protocolo (incluyendo las visitas 28 días y 3 meses después de la última dosis de cualquiera de los fármacos y 120 días después de la última dosis de atezolizumab, la que sea posterior) o la fecha en la que se reciben los últimos datos del último paciente requeridos para el análisis estadístico, la fecha que sea posterior, salvo que el paciente haya discontinuado prematuramente el estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 40
    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)
    Currently, the Sponsor does not have any plans to provide RO6874281 or any other study treatments or interventions to the participants after the end of the study or when participants discontinue or have been withdrawn from the study. The Sponsor will evaluate whether to continue providing RO6874281 to participants after the main study is over, in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product.
    Actualmente, el promotor no tiene ningún plan para proporcionar RO6874281 o cualquier otro tratamiento o intervención del ensayo a los participantes después de la terminación del estudio o cuando los participantes discontinúen o sean retirados del estudio. El promotor evaluará si continua proporcionando RO6874281 a los participantes una vez el ensayo principal haya acabado de acuerdo con la política global de Roche de acceso continuado a los productos en fase de 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 Decision2017-12-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-22
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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