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    Summary
    EudraCT Number:2017-004566-99
    Sponsor's Protocol Code Number:CO39612
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-07-09
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-004566-99
    A.3Full title of the trial
    A PHASE Ib/II, OPEN-LABEL, MULTICENTER, RANDOMIZED UMBRELLA STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE IMMUNOTHERAPY-BASED TREATMENT COMBINATIONS IN PATIENTS WITH METASTATIC COLORECTAL CANCER (MORPHEUS-CRC)
    ESTUDIO EN PARAGUAS DE FASE IB/II, ABIERTO, MULTICÉNTRICO, ALEATORIZADO QUE EVALÚA LA EFICACIA Y LA SEGURIDAD DE MÚLTIPLES COMBINACIONES DE TRATAMIENTOS BASADOS EN INMUNOTERAPIA EN PACIENTES CON CÁNCER COLORRECTAL METASTÁSICO (MORPHEUS-CCR)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients with Metastatic Colorectal Cancer (Morpheus-CRC)
    Estudio para evaluar la eficacia y seguridad de multiples combinaciones de tratamientos basados en inmunoterapia en pacientes con cáncer colorectal metastasico (Morpheus-CCR)
    A.4.1Sponsor's protocol code numberCO39612
    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 SponsorF. 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 code4047
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+34913257300
    B.5.5Fax number+34913248195
    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 Yes
    D.2.1.1.1Trade name TECENTRIC
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 nameAtezolizumab
    D.3.2Product code RO5541267
    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 INNATEZOLIZUMAB
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameTECENTRIC
    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.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 AVASTIN
    D.2.1.1.2Name of the Marketing Authorisation holderEU/1/04/300/002
    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 nameBEVACIZUMAB
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 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 nameCOBIMETINIB
    D.3.2Product code RO5514041
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCOBIMETINIB
    D.3.9.2Current sponsor codeRO5514041
    D.3.9.3Other descriptive nameCOBIMETINIB HEMIFUMARATE
    D.3.9.4EV Substance CodeSUB168371
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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 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 nameIMPRIME PGG
    D.3.2Product code RO7234832
    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 INNImprime PGG
    D.3.9.3Other descriptive namePGG BETA GLUCAN
    D.3.9.4EV Substance CodeSUB30829
    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 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: 5
    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 nameISATUXIMAB
    D.3.2Product code RO7268598
    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 INNISATUXIMAB
    D.3.9.2Current sponsor codeRO7268598
    D.3.9.3Other descriptive nameSAR650984
    D.3.9.4EV Substance CodeSUB187359
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 STIVARGA
    D.2.1.1.2Name of the Marketing Authorisation holderBayer AG
    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 nameREGORAFERIB
    D.3.2Product code RO7069680
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNREGORAFENIB
    D.3.9.1CAS number 755037-03-7
    D.3.9.2Current sponsor codeRO7069680
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.9.4EV Substance CodeSUB73090
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    Colorectal cancer (CRC)
    Cancer colorectal (CCR)
    E.1.1.1Medical condition in easily understood language
    CRC is the development of cancer from the colon or rectum (parts of the large intestine)
    El CCR es el desarrollo del cáncer desde el colon o el recto (partes del intestino grueso)
    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 10052362
    E.1.2Term Metastatic colorectal cancer
    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 the efficacy (objective response) of immunotherapy-based treatment combinations
    • To evaluate the safety of immunotherapy-based treatment combinations
    • Evaluar la eficacia (respuesta objetiva) de las combinaciones de tratamientos basados en inmunoterapias
    •Evaluar la seguridad de las combinaciones de tratamientos basados en inmunoterapias
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy (progression free survival, overall survival, overall survival at specific time points, duration of response, and disease control) of immunotherapy-based treatment combinations
    • To characterize the pharmacokinetic profile of drugs that are administered as part of an immunotherapy-based treatment combination
    • To evaluate the immune response (immunogenicity) to drugs that are administered as part of an immunotherapy-based treatment combination
    • Evaluar la eficacia (supervivencia libre de progresión, supervivencia global, supervivencia global en puntos temporales específicos, duración de la respuesta y control de la enfermedad) de las combinaciones de tratamientos basados en inmunoterapias
    • Establecer el perfil farmacocinético de los fármacos que se administran como parte de una combinación de tratamientos basados en inmunoterapias
    • Evaluar la respuesta inmunitaria (inmunogenicidad)a los fármacos que se administran como parte de una combinación de tratamientos basados en inmunoterapias
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Age >=18 years
    -Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
    -Life expectancy >= 3 months, as determined by the investigator
    -Disease progression during or following two separate lines of treatment for mCRC that consisted of fluoropyrimidine-, oxaliplatin-, or irinotecan-containing chemotherapy in combination with a biologic agent
    -Availability of a representative tumor specimen that is suitable for determination of Programmed cell Death-1 (PD-L1) and/or additional biomarker status by means of central testing
    -Measurable disease according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
    -Adequate hematologic and end-organ function
    -For patients receiving therapeutic anticoagulation: stable anticoagulant regimen during the 14 days prior to initiation of study treatment
    -Negative HIV test and hepatitis B surface antigen test at screening
    -Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
    - Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
    - Tumor accessible for biopsy
    - For women and men: agreement to remain abstinent or use contraceptive measures as outlined for each specific treatment arm
    -Edad ≥ 18 años
    -Estado funcional de 0 o 1 en la escala ECOG
    -Esperanza de vida ≥ 3 meses, determinada por el investigador
    -Evolución de la enfermedad durante o después de dos líneas de tratamiento independientes para el CCRm en las que se administró quimioterapia con fluoropirimidina, oxaliplatino o irinotecán en combinación con un fármaco biológico
    -Disponibilidad de una muestra de tumor representativa que sea adecuada para determinar la expresión de PD-L1 o el estado de otros biomarcadores mediante una prueba central
    -Enfermedad cuantificable según los criterios RECIST v. 1.1
    -Función hemática y del órgano afectado adecuada
    -Para los pacientes que reciban tratamiento con anticoagulantes: régimen estable de anticoagulantes durante los 14 días previos al inicio del tratamiento del estudio
    -Resultado negativo en el VIH y en la prueba del antígeno de superficie del virus de la hepatitis B en el momento de la selección
    -Resultado negativo total en la prueba de anticuerpos contra el núcleo de la hepatitis B (HBcAb) en el momento de la selección, o resultado positivo en la prueba del HBcAb total seguido de un resultado negativo en la prueba de ADN del virus de la hepatitis B (VHB) en la selección
    -Resultado negativo en la prueba del virus de la hepatitis C (VHC) o resultado positivo en la prueba de anticuerpos contra el VHC seguido de un resultado negativo en la prueba de ARN del VHC en el momento de la selección
    -Tumor accesible para biopsia
    -Para mujeres y hombres: acceder a mantenerse en abstinencia o utilizar los métodos anticonceptivos indicados para cada grupo de tratamiento específico
    E.4Principal exclusion criteria
    -High microsatellite instability tumor
    -Mutation in the BRAF oncogene
    -Prior treatment with any of the protocol-specified study treatments with the exception of patients who received bevacizumab for treatment of CRC.
    -Prior allogeneic stem cell or solid organ transplantation
    -Symptomatic, untreated, or actively progressing central nervous system metastases
    -History of leptomeningeal disease
    -Active or history of autoimmune disease or immune deficiency, idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
    -History of malignancy other than CRC within 2 years prior to screening
    -Active tuberculosis
    -Severe infection within 4 weeks prior to initiation of study treatment
    -Significant cardiovascular disease
    -Grade >= 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment
    -Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
    -Adverse events from prior anti-cancer therapy that have not improved to Grade <= 1 or better, with the exception of alopecia of any grade and Grade <= 2 peripheral neuropathy
    -Tumor de inestabilidad de microsatélites alta
    -Mutación en el oncogén BRAF
    -Tratamiento anterior con alguno de los tratamientos del estudio indicados en el protocolo, con la excepción de pacientes que reciben bevacizumab para el tratamiento de la CCR
    -Alotrasplante de células madre o trasplante de órganos sólidos previos
    -Metástasis del SNC sintomática, no tratada o con evolución activa.
    -Antecedentes de enfermedad leptomeníngea
    -Antecedentes de fibrosis pulmonar idiopática, neumonía organizada, neumonitis provocada por fármacos, neumonitis idiopática o indicios de neumonitis activa en la tomografía axial computarizada (TAC) de tórax obtenida durante la selección.
    -Antecedentes de neoplasia maligna distinta al CCR en los 2 años anteriores a la selección
    -Tuberculosis activa
    -Infección grave en las 4 semanas anteriores al inicio del tratamiento del estudio
    -Cardiovasculopatía significativa
    -Hemorragia de grado ≥ 3 o episodio hemorrágico en los 28 días previos al inicio del tratamiento del estudio
    -Procedimiento quirúrgico importante para fines distintos al diagnóstico en las 4 semanas anteriores al inicio del tratamiento del estudio o previsión de necesitar un procedimiento quirúrgico importante durante el transcurso del estudio
    -Acontecimientos adversos a causa de un tratamiento antineoplásico anterior que no haya mejorado a grado ≤ 1 o mejor, con la excepción de la alopecia de cualquier grado y la neuropatía periférica de grado ≤ 2
    E.5 End points
    E.5.1Primary end point(s)
    1. Objective response rate
    2. Incidence, nature, and severity of adverse events and laboratory abnormalities
    3. Change from baseline in vital signs and ECG parameters
    4. Change from baseline in targeted clinical laboratory test results
    1. Tasa de respuesta objetiva
    2. Incidencia, naturaleza, y severidad de los acontecimientos adversos y las anormalidades de laboratorio
    3. Cambios desde basal en signos vitales y parámetros de ECG
    4. Cambio desde basal en los resultados clinicos diana de laboratorio
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. From Randomization until disease progression or loss of clinical benefit (up to 5 years)
    2-4. From first study treatment administration until 30 days after the last dose or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to 5 years)
    1. Desde randomizacion hasta progresión de la enfermedad o perdida de beneficio clínico (hasta un máximo de 5 años).
    2-4. Desde la primera administración de tratamiento del ensayo hasta 30 días después de la ultima dosis o hasta el inicio de nuevas terapias anticancerígenas sistémicas, lo que ocurra antes (hasta un máximo de 5 años)
    E.5.2Secondary end point(s)
    1. Progression-free survival
    2. Overall survival after randomization
    3. Overall survival at specific time points
    4. Duration of response
    5. Disease control rate
    6. Plasma or serum concentration of each drug at specified time points
    7. Presence of antidrug antibody (ADAs) during the study relative to the presence of ADAs at baseline
    1. Supervivencia libre de progresión
    2. Supervivencia global después de la randomización
    3. Superviviencia global en puntos temporales específicos
    4. Duración de la respuesta
    5. Tasa de control de la enfermedad
    6. Concentración en plasma o suero de cada fármaco en puntos temporales específicos.
    7. Presencia de anticuerpos antifármaco (AAF) durante el ensayo referidos a la presencia de AAFs en basal.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. From randomization to the first occurrence of disease (up to 5 years)
    2. From randomization to death from any cause (up to 5 years)
    3. Month 6
    4. From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 5 years)
    5. From randomization until disease progression or loss of clinical benefit (up to 5 years)
    6-7. During treatment and at treatment discontinuation
    1. Desde randomizacion a la primera recurrencia de la enfermedad (hasta un máximo de 5 años)
    2. Desde randomización a muerte por cualquier causa (hasta un máximo de 5 años)
    3. Mes 6
    4. desde la fecha de la primera ocurrencia de una respuesta objetiva documentada a progresión de la enfermedad o muerte por cualquier causa, la que ocurra antes (hasta un máximo de 5 años)
    5. Desde randomizacion hasta progresión de la enfermedad o perdida de beneficio clínico (hasta un máximo de 5 años)
    6-7. Durante el tratamiento y en la discontinuación del 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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    phase Ib/II multiple drug combination
    Fase Ib/II de combinacion de multiples fármacos
    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 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) 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    France
    Korea, Republic of
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of this study is defined as the date when the last patient completes the last visit in both stages, including survival follow-up visits conducted by telephone or on-site visit. The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 3-5 years.
    El final de este estudio se define como la fecha en la que el último paciente lleva a cabo la última visita de ambas fases, incluidas las visitas de seguimiento de la supervivencia realizadas por teléfono o en la clínica. La duración total del estudio desde la selección del primer paciente hasta el final del estudio se espera que sea de aproximadamente 3-5 años
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    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: 72
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 48
    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 state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 56
    F.4.2.2In the whole clinical trial 120
    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 the Roche IMPs (atezolizumab, bevacizumab, or cobimetinib) or any other study treatments or interventions to patients who have completed the study. The Sponsor may evaluate whether to continue providing atezolizumab, cobimetinib, and bevacizumab in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product,
    http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    Actualmente, el promotor no tiene planes de proporcionar los IMPs de Roche (atezolizumab, bevacizumab o cobimetinib) o cualquier otro tratamiento o intervencion del estudio a pacientes que han completado el ensayo. El promotor podrá evaluar si continua proporcionando atezolizumab, cobimetinib y bevacizumab de acuerdo con la política global de Roche de acceso continuado a fármacos en investigación, http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    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 Decision2018-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-22
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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