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    Summary
    EudraCT Number:2016-004529-17
    Sponsor's Protocol Code Number:YO39609
    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:2018-02-12
    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 number2016-004529-17
    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 LOCALLY ADVANCED UNRESECTABLE OR METASTATIC GASTRIC OR GASTROESOPHAGEAL JUNCTION CANCER (MORPHEUS-GASTRIC CANCER)
    ESTUDIO EN PARAGUAS, EN FASE Ib/II, ABIERTO, MULTICÉNTRICO Y ALEATORIZADO PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DE COMBINACIONES DE TRATAMIENTOS BASADOS EN MÚLTIPLES INMUNOTERAPIAS EN PACIENTES CON CÁNCER GÁSTRICO O DE LA UNIÓN GASTROESOFÁGICA LOCALMENTE AVANZADO IRRESECABLE O METASTÁSICO (MORPHEUS-CÁNCER GÁSTRICO)
    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 Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer (Morpheus-Gastric Cancer)
    Estudio para la evaluacion de la eficacia y seguridad de combinación de
    tratamientos basados en multiples inmunoterapias en pacientes con cáncer gástrico o de la unión gastroesofágica localmente avanzado irresecable o metastásico (Morpheus-Cancer Gástrico)
    A.4.1Sponsor's protocol code numberYO39609
    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. Hoffman-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. Hoffman-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 number34913257300
    B.5.5Fax number34913248196
    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 nameAtezolizumab
    D.3.2Product code RO5541267
    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.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 nameCobimetinib (GDC-0973)
    D.3.2Product code RO5514041
    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 INNCobimetinib
    D.3.9.2Current sponsor codeRO5514041
    D.3.9.3Other descriptive nameCOBIMETINIB
    D.3.9.4EV Substance CodeSUB122319
    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: 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 nameBL8040
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBL-8040
    D.3.9.2Current sponsor codeBL-8040
    D.3.9.3Other descriptive nameRO7200024
    D.3.9.4EV Substance CodeSUB187495
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number73
    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 namePEGPH20
    D.3.2Product code RO7200028
    D.3.4Pharmaceutical form Solution for injection
    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 INNPEGPH20
    D.3.9.2Current sponsor codeRO7200028
    D.3.9.3Other descriptive namePEGPH20
    D.3.9.4EV Substance CodeSUB33062
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.3
    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: 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 Trajenta
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International 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 nameTrajenta
    D.3.2Product code RO5289421
    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 INNTrajenta
    D.3.9.1CAS number 668270-12-0
    D.3.9.2Current sponsor codeRO5289421
    D.3.9.3Other descriptive nameLINAGLIPTIN
    D.3.9.4EV Substance CodeSUB31340
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 Cyramza
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    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 nameCyramza
    D.3.2Product code Ro7234952
    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 INNRamucirumab​
    D.3.9.1CAS number 947687-13-0
    D.3.9.2Current sponsor codeRO723-4952
    D.3.9.3Other descriptive nameRAMUCIRUMAB
    D.3.9.4EV Substance CodeSUB32795
    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 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: 7
    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 Sindaxel
    D.2.1.1.2Name of the Marketing Authorisation holderActavis S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationRomania
    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 nameSindaxel
    D.3.2Product code RO0247506
    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.3.9.2Current sponsor codeRO024-7506
    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.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
    Locally advanced unresectable or Metastatic gastric or gastroesophageal junction cancer
    CÁNCER GÁSTRICO O DE LA UNIÓN GASTROESOFÁGICA LOCALMENTE
    AVANZADO IRRESECABLE O METASTÁSICO
    E.1.1.1Medical condition in easily understood language
    Gastric cancer is a disease in which malignant (cancer) cells form in the lining of the stomach
    El cancer gastrico es una enfermedad en la cual celulas malignas (cancer) se forman en el revestimiento del estómago
    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
    •To evaluate the efficacy (including Objective Response) of immunotherapy based treatment combinations in all arms during Stage 1
    Evaluar en todos los grupos la eficacia (incluyendo la respuesta objetiva) de las combinaciones de tratamientos basados en inmunoterapia durante la fase 1
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy (including Progression-free survival [PFS] after randomization, Overall survival [OS] after randomization, OS at specific timepoints [e.g., 6 and 12 months], Duration of response and Disease control) of immunotherapy based treatment combinations in all arms during Stage 1
    •To evaluate the efficacy of immunotherapy based treatment combinations in all arms during Stage 1 and Stage 2
    •To evaluate the safety of immunotherapy-based treatment combinations in all arms during Stage 1 and during Stage 2
    •To identify the recommended dose of cobimetinib in combination with atezolizumab and mFOLFOX6 (Arm A of the First-Line [1L] Cohort) during Stage 1
    •To characterize the PK profile of drugs that are administered as part of an immunotherapy-based treatment combination during Stage 1 and Stage 2
    •To evaluate the immune response to drugs that are administered as part of an immunotherapy-based treatment combination during Stage 1 and Stage 2
    •Evaluar la eficacia ( incluyendo la SSP) tras la aleatorización, SG tras la
    aleatorizacion, SG en puntos temporales específicos (ej.6 y 12 meses), Duración de a respuesta y control de la enfermedad de las combinaciones de tratamientos basados en inmunoterapia durante la fase 1. -Evaluar la eficacia de las combinaciones de tratamientos basados en inmunoterapia en todos los grupos durante las fases 1 y 2. -Evaluar la seguridad de las combinaciones de tratamientos
    basados en inmunoterapia en todos los grupos durante las fases 1 y 2 -Determinar la dosis recomendada de cobimetinib en combinación con atezolizumab y mFOLFOX6 (grupo A de la cohorte de primera línea) -Establecer el perfil farmacocinético de fármacos que se administran como parte de una combinación de tratamientos basados en inmunoterapia durante las fases 1 y 2 -Evaluar la respuesta inmunitaria a los fármacos que se administran como parte de una
    combinación de tratamientos basados en inmunoterapia durante las fases 1 y 2
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria for Stages 1 and 2
    - Ability to comply with the study protocol, in the investigator’s judgment
    - Measurable disease (at least one target lesion) according to Response Evaluation Criteria in Solid Tumors, Version (RECIST) v1.1
    - Adequate hematologic and end organ function
    - Negative HIV test at screening
    - Negative 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 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 of childbearing potential: agreement to remain abstinent or use contraceptive measures as outlined for each specific treatment arm
    - For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
    Inclusion Criteria for Stage 1
    - Age >=18 years at the time of signing Informed Consent Form
    - ECOG Performance Status of 0 or 1
    - Life expectancy >3 months, as determined by the investigator
    - Histologically or cytologically confirmed locally advanced unresectable or metastatic adenocarcinoma of gastric or gastroesophageal junction
    - Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status by means of central testing
    - Only for the 1L Cohort: patients whose tumors are without HER2 amplification documented by fluorescence in situ hybridization (FISH) or in situ hybridization (ISH) or are negative by immunohistochemistry (IHC) 0 or +1 on previously collected and assessed tumor tissue upon initial diagnosis of disease by local laboratory testing
    Inclusion Criteria for Stage 2
    - Eastern Cooperative Oncology Group (ECOG) Performance Status of 02
    - Participation in the 2L Cohort during Stage 1
    - Patients in a control arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity, provided that Medical Monitor approval for entry into Stage 2 is obtained, or disease progression per RECIST v1.1 while receiving treatment
    - Patients in an experimental arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related to atezolizumab, provided that Medical Monitor approval for entry into Stage 2 is obtained, or loss of clinical benefit as determined by the investigator while receiving treatment
    - Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 (if deemed clinically feasible by the investigator) because of unacceptable toxicity, disease progression per RECIST v1.1, or loss of clinical benefit as determined by the investigator
    -Criterios de inclusión para las fases 1 y 2
    -Capacidad para cumplir con el protocolo del estudio a juicio del investigador
    -Enfermedad cuantificable (al menos una lesion indicadora) según el RECIST v. 1.1
    -Función hemática y del órgano afectado adecuada
    -Prueba negativa de VIH en la seleccion
    -Prueba del antígeno de superficie de la hepatitis B (HBsAg) negativa en la selección
    -Prueba del antígeno central de la hepatitis B (HBcAb) total negativa en la selección o prueba del HBcAb total positiva seguida de una prueba de ADN del virus de la hepatitis B (VHB) negativa en la selección
    -Prueba de anticuerpos del VHC negativa en la selección o prueba de anticuerpos del VHC positiva seguida de una prueba de ARN del VHC negativa en la selección
    -Tumor accesible para biopsia
    Para mujeres en edad fértil: acceder a mantenerse en abstinencia o a utilizar los métodos anticonceptivos indicados para cada grupo de tratamiento específico
    Para hombres: acceder a mantenerse en abstinencia (abstenerse del coito heterosexual) o a utilizar métodos anticonceptivos, y acceder a no donar esperma Criterios de inclusión para la fase
    Criterios de inclusion para Fase1
    - Edad> = 18 años en el momento de la firma del formulario de consentimiento informado
    - ECOG P Estado funcional según el ECOG de 0 o 1erformance Status of 0 or 1
    -Esperanza de vida # 3 meses, determinada por el investigador.
    -Adenocarcinoma localmente avanzado, irresecable o metastásico, histológicamente o citológicamente confirmado, de unión gástrica o gastroesofágica
    -Disponibilidad de una muestra de tumor representativa que sea adecuada para determinar los niveles de PD-L1 y/o el estado de otros biomarcadores mediante una prueba central
    -Solo para la cohorte 1L: los pacientes cuyos tumores no presenten amplificación del gen HER2 según las pruebas de hibridación fluorescente in situ (FISH) o hibridación in situ (ISH) o den un resultado negativo de 0 o + 1 en las pruebas de inmunohistoquímica (IHQ) de tejidos tumorales previamente recogidos y evaluados por un laboratorio local de pruebas analíticas tras el diagnóstico inicial de la enfermedad _
    Criterios de inclusión para la fase 2
    Estado funcional según el ECOG de 0-2.
    Participación en la Cohorte 2L durante la Etapa 1
    Pacientes en un grupo de control durante la fase 1: poder iniciar el tratamiento de la fase 2 durante los 3 meses posteriores tras presentar una toxicidad inaceptable, siempre que se obtenga la autorización del monitor médico para participar en la fase 2, o se observe progresión de la enfermedad según el RECIST v. 1.1 durante el tratamiento
    Pacientes en un grupo experimental durante la fase 1: poder iniciar el
    tratamiento de la fase 2 durante los 3 meses posteriores tras presentar una
    toxicidad inaceptable no relacionada con atezolizumab, siempre que se obtenga la
    autorización del monitor médico para participar en la fase 2, o si hubiera pérdida de
    beneficios clínicos durante el tratamiento, según lo determine el investigador.
    Disponibilidad de una muestra de tumor procedente de una biopsia realizada tras
    la interrupción de la fase 1 (si el investigador lo considera factible desde un punto
    de vista clínico) debido a una toxicidad inaceptable, progresión de la enfermedad según el RECIST v. 1.1, o pérdida de beneficios clínicos, según lo determine el investigador.


    E.4Principal exclusion criteria
    Exclusion Criteria for Stages 1 and 2
    - Prior treatment with any of the protocol-specified study treatments, with the exception of chemotherapy, radiotherapy, and atezolizumab given in Stage 1
    - Patients with a signet ring cells dominant carcinoma (>50% of the tumor)
    - Weight loss >5% within 4 weeks prior to screening
    - Uncontrolled pleural effusion, pericardial effusion, or ascites
    - Uncontrolled tumor-related pain
    - Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
    - Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
    - History of leptomeningeal disease
    - Active or history of autoimmune disease or immune deficiency
    - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
    - Known clinically significant liver disease
    - Active tuberculosis
    - Treatment with therapeutic oral or intravenous antibiotics within 2 weeks prior to initiation of study treatment
    - Significant cardiovascular disease within 12 months prior to initiation of study treatment, or unstable arrhythmia or unstable angina within 3 months prior to initiation of study treatment
    - Significant bleeding disorder, vasculitis, Grade >=3 hemorrhage, or significant bleeding episode from a gastrointestinal tract event within 3 months prior to initiation of study treatment
    - History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism within 3 months prior to initiation of study treatment
    - Prior allogeneic stem cell or solid organ transplantation
    - Treatment with anticoagulation with warfarin, low-molecular-weight heparin, or similar agents for therapeutic purposes
    - History of malignancy other than gastric or gastroesophageal junction carcinoma within 2 years prior to screening
    - History of severe allergic, anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
    - Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene polymorphism predisposing the patient to 5-FU toxicity
    - Treatment with systemic immunostimulatory medication within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initiation of study treatment
    - Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment
    Exclusion Criteria for 2L Cohort, Stage 1
    - Urinary protein is >1 + on dipstick and the required following 24-hour urine collection shows urinary protein >2000 mg
    - Serious or non-healing wound, peptic ulcer, or bone fracture within 28 days prior to initiation of study treatment
    - History of gastrointestinal perforation and/or fistulae within 6 months prior to initiation of study treatment
    - Presence of a bowel obstruction, history or presence of inflammatory enteropathy, or extensive intestinal resection, Crohn disease, ulcerative colitis, or chronic diarrhea
    - Uncontrolled arterial hypertension >=140/>=95 mmHg despite standard medical management
    - Chronic therapy with non-steroidal anti-inflammatory agents
    Exclusion Criteria for Stage 1
    - Systemic treatment for gastric cancer within 2 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
    - Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
    - Treatment with investigational therapy within 28 days prior to initiation of study treatment
    - Patients with Type 2 diabetes mellitus currently under treatment with DPP 4 inhibitors
    - Known dihydropyrimidine dehydrogenase deficiency
    Exclusion Criteria for Arms Containing Cobimetinib during Stages 1 and 2
    - Prior treatment with MAPK inhibitors (including cobimetinib)
    - Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
    - Inability to tolerate atezolizumab during Stage 1
    - Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or below 50%, whichever is lower
    - History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
    Exclusion Criteria for Atezo + PEGPH20 Arm during Stage 1
    - Treatment with megestrol acetate within 10 days prior to initiation of study treatment
    - Contraindication to heparin as per institutional guidelines
    Criterios de exclusión para las fases 1 y 2
    Tto previo con alguno de los ttos del estudio indicados en el protocolo, con la excepción de quimioterapia, radioterapia y administración de atezolizumab en la fase 1.
    Pac que presenten un carcinoma con células en anillo de sello.
    Pérdida de peso de > 5 % en las 4 semanas previas a la selección
    Derrame pleural, derrame pericárdico o ascitis no controlados
    Dolor no controlado relacionado con el tumor.
    Hipercalciemia no controlada o hipercalciemia sintomática que requiera el uso continuado de tto con bisfosfonato
    Metástasis del sistema nervioso central (SNC) sintomática, sin tratar o con progresión activa.
    Ancedentes de enfermedad leptomeníngea
    Enfermedad autoinmunitaria activa o antecedentes
    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
    Ant de hepatopatía significativa desde un punto de vista clínico
    Tuberculosis activa
    Tto con antibióticos ter por vía oral o intravenosa (i.v.) en las 2 semanas antal inicio del tto
    Cardiovasculopatía significativa en los 12 meses anteriores al inicio del tto , o arritmia inestable o angina inestable en los 3 meses anteriores al inicio del tto
    Trastornos hemorrágicos significativos, vasculitis, hemorragia de grado = 3 o hemorragia significativa debidos a una complicación en el tubo gastrointestinal en los 3 meses previos al inicio del tto
    Ant de trombosis venosa profunda, embolia pulmonar u otra tromboembolia significativa en los 3 meses previos al inicio del tto
    Alotrasplante de células madre o trasplante de órganos sólidos previos
    Tto anticoagulante con warfarina, heparina de bajo peso molecular o fármacos similares con fines terapéuticos
    Ant de neoplasias malignas distintas al carcinoma gástrico o de la unión gastroesofágica en los 2 años anteriores a la selección
    Ant de reacciones alérgicas anafilácticas graves a anticuerpos híbridos o humanizados o proteínas de fusión
    Ant de deficiencia de dihidropirimidina deshidrogenasa o polimorfismos en el gen de la timidilato sintasa que predispongan al paciente a toxicidad a 5-FU
    Tto con fármacos imunoestimulantes sistémicos en las 4 semanas o 5semividas del fármaco (lo que sea más largo) previas al inicio del tto
    Tto con inmunodepresores sistémicos en las 2 semanas previas al inicio del tto
    Criterios de exclusión para la cohorte 2L, etapa 1
    Proteína urinaria > 1 + en el análisis con tira reactiva y proteína urinaria > 2000 mg en la muestra de orina requerida obtenida a las 24 horas
    Herida grave o que no cicatriza, úlcera péptica o fractura ósea en los 28 días previos al inicio del tratamiento del estudio
    Antecedentes de perforación gastrointestinal y/o fístulas en los 6 meses previos al inicio del tratamiento del estudio.
    Obstrucción intestinal, antecedentes o presencia de enteropatía inflamatoria, o extirpación intestinal importante enfermedad de Crohn, colitis ulcerosa o diarrea crónica.
    Hipertensión arterial no controlada = 140/ =95 mmHg, a pesar de recibir el tratamiento médico estándar.
    Therapy with non-steroidal anti-inflammatory agents
    Criterios de exclusión para la Etapa 1
    Tratamiento sistémico del cáncer gástrico en las 2 semanas o cinco semividas del fármaco previas al inicio del tratamiento del estudio
    -Tratamiento anterior con bloqueo de puntos de control inmunitario o coestimuladores de linfocitos T, incluidos los anticuerpos terapéuticos anti-CTLA-4, anti-PD-1 y anti-PD-L1
    Tratamiento con fármacos experimentales en los 28 días previos al inicio del tratamiento del estudio

    Antecedentes de deficiencia de dihidropirimidina deshidrogenasa
    Pacientes con diabetes mellitus de tipo 2 que estén bajo tratamiento con inhibidores de DPP-4.
    Antecedentes de deficiencia de dihidropirimidina deshidrogenasa
    Criterios de exclusión para armas que contienen Cobimetinib durante las Etapas 1 y 2
    Tratamiento previo con inhibidores de la MAPK (incluido cobimetinib)
    Incapacidad para tragar medicamentos o problemas de absorción insuficiente que podrían alterar la absorción de medicamentos administrados por vía oral
    Incapacidad para tolerar atezolizumab durante la fase 1
    Fracción de eyección ventricular izquierda por debajo del límite inferior de la normalidad institucional o inferior al 50 %, el valor que sea más bajo
    Antecedentes o indicios de patologías retinianas durante el examen oftalmológico que se consideren un factor de riesgo de desprendimiento de retina neurosensorial, coriorretinopatía serosa central, oclusión de la vena retiniana (OVR) o degeneración macular neovascular
    Criterios de exclusión para el grupo de atezo + PEGPH20 durante la fase 1
    Tto con acetato de megestrol en los 10 días previos al inicio del tratamiento del estudio
    Contraindicación del uso de heparina conforme a las directrices institucionales
    E.5 End points
    E.5.1Primary end point(s)
    Objective response
    Respuesta objetiva
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 5 years
    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 timepoints
    4. Duration of response
    5. Disease control
    6. Incidence, nature, and severity of adverse events and laboratory abnormalities, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0
    7. Change from baseline in vital signs, ECG parameters, and targeted clinical laboratory test results
    8. Occurrence and severity of study treatment-related adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0
    9. Plasma or serum concentration of each drug at specified timepoints
    10. Presence of anti-drug antibodies (ADAs) during the study relative to the presence of ADAs at baseline
    .1Supervivencia sin progresión
    2. Supervivencia global tras la aleatorización
    3. SG en puntos temporales específicos
    4. Duración de la respuesta
    5. Control de la enfermedad
    6. Incidencia, carácter y gravedad de los acontecimientos adversos y
    alteraciones analíticas, siendo la gravedad determinada con arreglo a los Criterios terminológicos comunes para acontecimientos adversos del Instituto Nacional contra el Cáncer de los EE. UU, versión 4.0. 7. Cambio respecto al valor basal en las constantes vitales, parámetros de ECG y resultados de las pruebas específicas de laboratorio.
    8. Incidencia y gravedad de los acontecimientos adversos debidos al
    tratamiento del estudio, siendo la gravedad determinada con arreglo a los Criterios terminológicos comunes para acontecimientos adversos del Instituto Nacional contra el Cáncer de los EE. UU, versión 4.0 9. Concentración en plasma o suero de cada fármaco en puntos temporales específicos 10. Presencia de AAF durante el
    estudio relativa a la presencia de AAF en el momento basal
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-2. Up to 5 years
    3. At 6 and 12 months
    4-8. Up to 5 years
    9. Day 1 and Day 15 of Cycle 1; Day 1 of Cycle 2, Cycle 3, Cycle 4, Cycle 8, Cycle 12 and Cycle 16; at time of loss of clinical benefit as determined by the investigator, at treatment discontinuation and 120 days after last dose of atezolizumab
    10. Day 1 of Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 8, Cycle 12 and Cycle 16; at treatment discontinuation and 120 days after last dose of atezolizumab
    1-2 Hasta un maximo de 5 dias 3. A los 6 y 12 meses 4-8. Hasta un maximo de 5 años 9. Dia 1 y dia 15 del ciclo 1; Dia 1 de los ciclos 2, 3, 4, 8, 12 y 16; en el momento de la perdida de beneficio clinico determinado por el investigador, a la discontinuacion del tratamiento y 120 dias después de la ultima dosis de atezolizumab 1
    10. Dia 1 de los ciclos 1, 2, 3, 4, 8, 12 y 16, a la discontinuacion del tratamiento y 120 dias 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 Yes
    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
    Fase Ib
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the 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 EEA10
    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
    Germany
    Korea, Republic of
    Netherlands
    Spain
    Taiwan
    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, including survival follow-up visits conducted by telephone or onsite visit.
    El final de este estudio se define como la fecha en la que el último paciente lleva a cabo la última visita, incluidas las visitas de seguimiento de la supervivencia realizadas por teléfono o en la clínica.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 state23
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 85
    F.4.2.2In the whole clinical trial 100
    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
    atezolizumab, cobimetinib, or
    any other study treatments or interventions to patients who have
    completed the study.
    The Sponsor may evaluate whether to continue providing atezolizumab
    and cobimetinib
    in accordance with the Roche Global Policy
    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 Decision2018-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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