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    Summary
    EudraCT Number:2017-004634-28
    Sponsor's Protocol Code Number:WO39613
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-14
    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 number2017-004634-28
    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 CISPLATIN-INELIGIBLE PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL CARCINOMA AFTER FAILURE WITH PLATINUM-CONTAINING CHEMOTHERAPY (MORPHEUS-mUC)
    ESTUDIO EN PARAGUAS DE FASE IB / II, ABIERTO, MULTICÉNTRICO, ALEATORIZADO, QUE EVALÚA LA EFICACIA Y LA SEGURIDAD DE LAS COMBINACIONES DE TRATAMIENTOS BASADOS EN MÚLTIPLES INMUNOTERAPIAS EN PACIENTES CON CARCINOMA UROTELIAL LOCALMENTE AVANZADO O METASTÁSICO TRAS FRACASO DE TRATAMIENTO CON QUIMIOTERAPIA CON PLATINO (MORPHEUS-mUC)
    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 Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma After Failure with Platinum Containing Chemotherapy (Morpheus-mUC)
    Un estudio que evalúa la eficacia y seguridad de las combinaciones de tratamientos basados en inmunoterapia múltiple en pacientes inelegibles con cisplatino con carcinoma urotelial localmente avanzado o metastásico después del fracaso con quimioterapia que contiene platino (Morpheus-mUC)
    A.4.1Sponsor's protocol code numberWO39613
    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 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 Yes
    D.2.1.1.1Trade name Tecentriq
    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.3.4Pharmaceutical 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.3.9.1CAS number 1380723-44-3
    D.3.9.3Other descriptive nameATEZOLIZUMAB
    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 RoActemra
    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.3.4Pharmaceutical 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 INNtocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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: 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 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.3.4Pharmaceutical 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 INNlinagliptin
    D.3.9.1CAS number 668270-12-0
    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: 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 nameisatuximab
    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.3.9.3Other descriptive nameISATUXIMAB
    D.3.9.4EV Substance CodeSUB187359
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 nameniraparib
    D.3.4Pharmaceutical form Capsule
    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 INNniraparib
    D.3.9.3Other descriptive nameNIRAPARIB
    D.3.9.4EV Substance CodeSUB177208
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 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 nameHu5F9-G4
    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 INNHu5F9-G4
    D.3.9.3Other descriptive nameHU5F9‐G4
    D.3.9.4EV Substance CodeSUB187222
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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: 7
    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 nameenfortumab vedotin
    D.3.4Pharmaceutical form Lyophilisate 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 INNENFORTUMAB VEDOTIN
    D.3.9.3Other descriptive nameenfortumab vedotin
    D.3.9.4EV Substance CodeSUB185524
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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
    Urothelial carcinoma (UC)
    Carcinoma urotelial (UC)
    E.1.1.1Medical condition in easily understood language
    UC is a type of cancer that typically occurs in the bladder
    La CU es un tipo de cáncer que generalmente se presenta en la vejiga.
    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 10064467
    E.1.2Term Urothelial carcinoma
    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 of immunotherapy-based treatment combinations during Stage 1 based on Objective response rate
    -Evaluar la eficacia de las combinaciones de tratamientos basados en inmunoterapia durante la Etapa 1 en función de la tasa de respuesta objetiva
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of immunotherapy-based treatment combinations during Stage 1 based on progression-free survival, overall survival after randomization, overall survival rate at specific time points (e.g., 12 months), duration of response, Disease control
    • To evaluate the safety of immunotherapy-based treatment combinations during Stage 1 and Stage 2
    • To characterize the pharmacokinetic 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 de las combinaciones de tratamientos de inmunoterapia durante la Etapa 1 en función de la tasa de respuesta objetiva
    -Evaluar la seguridad de las combinaciones de tratamientos basados en inmunoterapia durante la Etapa 1 y la Etapa 2
    -Para caracterizar el perfil farmacocinético de los medicamentos que se administran como parte de una combinación de tratamiento basado en inmunoterapia durante la Etapa 1 y la Etapa 2
    -Para evaluar la respuesta inmune a los medicamentos que se administran como parte de una combinación de tratamiento basado en inmunoterapia durante la Etapa 1 y la Etapa 2
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Stage 1
    - Age >=18 years
    - Life expectancy >= 3 months, as determined by the investigator
    - Ineligible for cisplatin-based chemotherapy
    - Histologically documented, locally advanced or metastatic UC (M1, Stage IV)
    - No prior chemotherapy for inoperable, loally advanced or metastatic UC
    - Availability of a representative tumor specimen that is suitable for determination of Programmed death-ligand 1 (PD-L1) and/or additional biomarker status by means of central testing
    - Disease progression during or following treatment with no more than one platinum containing regimen for inoperable, locally advanced or metastatic UC or disease recurrence
    Stage 1 and Stage 2
    - Ability to comply with the study protocol, in the investigator’s judgment
    - Eastern Cooperative ncology Group Performance Status of 0 or 1
    - 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 at screening
    - Negative total hepatitis B core antibody (HBcAb) test or positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL at screening and 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 of childbearing potential: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating eggs as outlined for each specific treatment arm
    Stage 2
    - Patients in the atezolizumab control arm: ability to initiate Stage 2 treatment within 3 months after loss of clinical benefit as determined by the investigator while receiving control 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 or loss of clinical benefit as determined by the investigator while receiving Stage 1 treatment
    - Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1
    Criterios de inclusión para la fase 1
    -Edad ≥18 años
    -Esperanza de vida ≥3 meses, determinada por el investigador
    -No elegible para la quimioterapia basada en cisplatino
    -Documentado mediante pruebas histológicas CU metastásico (M1, estadio IV) o localmente avanzado
    -Sin quimioterapia previa para CU inoperable, muy avanzada o metastásica
    -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
    -Evolución de la enfermedad durante o después del tratamiento con no más de un régimen con platino para CU irresecable, localmente avanzado o metastásico o recurrencia de la enfermedad.
    Fase I y II
    -Capacidad para cumplir con el protocolo del estudio a juicio del investigador
    -Estado funcional de ECOG de 0 o 1
    -Enfermedad cuantificable (al menos una lesión indicadora) 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
    -Prueba de VIH negativa en el screening
    -Resultado negativo en la prueba de anticuerpos totales del núcleo de la hepatitis B (HBcAb) en la selección seguido de un resultado en la prueba de ADN del virus de la hepatitis B (VHB) <500 UI/ml en la selección o cuya cuya prueba de anticuerpos contra el VHC dé positivo.
    -Tumor accesible para biopsia
    -Para las mujeres y los hombres en edad fértil: acuerdo para permanecer abstinente o usar medidas anticonceptivas y acuerdo para abstenerse de donar óvulos como se describe para cada brazo de tratamiento específico
    Fase 2
    Pacientes asignados al grupo de control con atezolizumab: poder iniciar el tratamiento de la fase 2 en los 3 meses posteriores a la observación de pérdida de beneficios clínicos según lo determine el investigador mientras reciben el tratamiento de control
    -Pacientes de un grupo experimental durante la fase 1: poder iniciar el tratamiento de la fase 2 no más tarde de 3 meses tras padecer una toxicidad inaceptable no asociada a atezolizumab o pérdida de beneficios clínicos, según lo determine el investigador, mientras reciben el tratamiento de la fase 1
    -Disponibilidad de una muestra de tumor procedente de una biopsia realizada tras la interrupción de la fase 1
    E.4Principal exclusion criteria
    Stage 1
    - Prior treatment with a T-cell co-stimulating therapy or an immune checkpoint inhibitor including anti- CTLA-4 anti-PD-1, and anti-PD-L1 therapeutic antibodies
    - Prior treatment with any of the protocol-specified study treatments including treatment with any poly polymerase inhibitor, nectin-4 targeting agents, signal regulatory protein α-targeting agents, or agents that block CD38
    - Any approved anti-cancer therapy
    - Eligible only for the control arm
    Stage 1 and Stage 2
    - Prior allogeneic stem cell or solid organ transplantation
    - Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug prior to the initiation of study treatment
    - Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment
    - Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures and tumor-related pain
    - Uncontrolled or symptomatic hypercalcemia and symptomatic, untreated or actively progressing central nervous system metastases
    - History of leptomeningeal disease, autoimmune disease, 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 UC within 2 years prior to screening
    - Active tuberculosis (TB)
    - Severe infection within 4 weeks prior to initiation of study treatment
    - Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 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
    - Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug
    - History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins
    - Known intolerance or hypersensitivity to any of the study drugs or their excipients and any of the drugs required for premedication
    - Patients entering Stage 2: inability to tolerate atezolizumab during Stage 1
    - Pregnancy or breastfeeding, or intention of becoming pregnant during the study
    - Patients entering Stage 2: recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent
    For Atezo-EV Arm during Stage 1 and Stage 2
    - Ongoing sensory or motor neuropathy Grade >= 2
    - Active keratitis or corneal ulcerations
    - Uncontrolled diabetes
    - AST or ALT >= 3.0 × ULN
    - Evidence of active keratitis or corneal ulcerations during the Stage 1 and 2 ophthalmologic examination prior to Cycle 1, Day 1 will be re-assigned to the control arm and Atezo-Lina arm
    For Atezo-Nira Arm during Stage 1
    - Inability to swallow medication or a malabsorption condition that would alter the absorption of orally administered medications
    - Patients with uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome
    For Atezo-Hu5F9-G4 Arm during Stage 1
    - RBC transfusion dependence, defined as requiring more than 2 units of red blood cells transfused during the 4-week period prior to screening
    - History of hemolytic anemia or Evans syndrome in the last 3 months
    For Atezo-Lina Arm during Stage 1 and Stage 2
    - Known diagnosis of Type 1 diabetes mellitus and Type 2 diabetes mellitus currently under treatment with DPP-4 inhibitor
    - Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
    For Atezo-TCZ Arm during Stage 1
    - Preexisting central nervous system demyelinating or seizure disorders
    - History of diverticulitis, diverticulosis requiring antibiotic treatment, or other symptomatic lower gastrointestinal conditions that might predispose to perforations
    - Current liver disease unrelated to the underlying cancer diagnosis
    - Active current infection
    - Active TB requiring treatment within 3 years prior to baseline and untreated latent TB
    - Primary or secondary immunodeficiency
    Fase I
    -Tto anterior con un inhibidor del punto de control o coestimuladores de linfocitos T, incluidos los anticuerpos terapéuticos anti-CTLA-4, anti-PD-1 y anti-PD-L1
    -Tto anterior con alguno de los tratamientos del estudio indicados en el protocolo, incluido el tratamiento con cualesquiera conjugados anticuerpo-fármaco, inhibidores de la poli inhibidor de fármacos dirigidos a la nectina-4, fármacos dirigidos a la SIRPα o fármacos que bloqueen el CD38
    -Cualquier terapia anticáncer aprobada
    -Elegible solo para el brazo de control
    Fase 1 y 2
    -Alotrasplante de células madre o trasplante de órganos sólidos previos
    -Tto con fármacos inmunoestimulantes sistémicos en las cuatro semanas o cinco semividas del fármaco antes del inicio del tto
    Tto con inmunosupresores sistémicos en las 2 semanas previas al inicio del tratamiento del estudio, o previsión de que se necesite administrar inmunosupresores sistémicos
    -Derrame pleural incontrolado, derrame pericárdico o ascitis q requieran procedimientos de drenaje recurrentes
    -Hipercalcemia incontrolada o sintomática y metástasis en el sistema nervioso central sintomáticas, no tadas o en progreso activo
    -Ant de enfermedad leptomeníngea, enfer autoinmune, fibrosis pulmonar idiopática, neumonía organizada inducida por fármacos, neumonitis idiopática, o evidencia de neumonitis activa en la exploración de tomografía computarizada de tórax
    -Ant de neoplasia maligna distinta al CU en los 2 años anteriores a la selección
    -Tuberculosis activa
    -Infección grave en las 4 sem ant al inicio del tto -Tratamiento con antibióticos terapéuticos por vía oral o intravenosa (i.v.) en las dos semanas anteriores al inicio del tto
    -Cardiovasculopatía significativa
    -Hemorragia de grado ≥3 o episodio hemorrágico en los 28 días previos al inicio del tto
    -Proce quirúrgico importante para fines distintos al diagnóstico en las 4 semanas anteriores al inicio del tto o previsión de necesitar un proc quirúrgico importante durante el transcurso del estudio
    -Acon adversos a causa de un tto antineoplásico anterior q no haya mejorado a grado ≤1 o mejor, con la excepción de la alopecia de cualquier grado y la neuropatía periférica de grado ≤2
    Otra afección, disfunción metabólica, hallazgo en exploraciones físicas o hallazgos analíticos q contraindiquen el uso de un fármaco en investigación
    -Ant de reacciones alérgicas graves a anticuerpos híbridos o humanizados o a proteínas de fusión
    -Int o hipersensibilidad conocida a cualquiera de los fármacos del estudio o a sus excipientes
    -Ptes que vayan a participar en la fase 2: incapacidad de tolerar atezo durante la fase 1
    -Mujeres embarazadas o en período de lactancia, o con intención de quedarse embarazadas durante el estudio
    -Ptes que vayan a participar en la fase 2: recuperación de todos los acontecimientos adversos relacionados con la inmunoterapia hasta un grado 1 o mejor o como en el momento basal en el momento del consentimiento
    Los ptes que cumplan alguno de los siguientes criterios serán excluidos del grupo de Atezo+EV durante la fase 1 y 2: Neuropatía sensorial o motora en curso de grado ≥2, Queratitis activa o úlceras corneales,Diabetes no controlada, ASAT y ALAT ≥3,0 veces el LSN
    Evidencia de queratitis activa o ulceraciones de la córnea durante el examen oftalmológico de Etapa 1 y 2 antes del Ciclo 1, Día 1 se reasignará al brazo de control y al brazo de Atezo-Lina
    Para el grupo de Atezo+Nira durante la fase 1
    -Inca para tragar medicamentos o un problema de absorción insuficiente que podría alterar la absorción de medicamentos administrados por vía oral
    -Ptes con arritmia ventricular no controlada, trastorno convulsivo importante no controlado, compresión medular inestable, o síndrome de la vena cava superior
    Para el grupo de Atezo+Hu5F9-G4 durante la fase 1
    Depen de transfusiones de eritrocitos, definida como la necesidad de transfusión de más de 2 unidades de eritrocitos durante el periodo de 4 semanas previo a la selección
    Ant de anemia hemolítica o síndrome de Evans en los últimos 3 meses
    Para el grupo de Atezo+Lina durante la fase 1 y la fase 2
    Diagnóstico conocido de diabetes mellitus de tipo 1
    • Diagnóstico conocido de diabetes mellitus de tipo y 2 bajo tratamiento con inhibidores de DPP-4
    Incapacidad para tragar medicamentos o problemas de absorción insuficiente que podrían alterar la absorción de medicamentos administrados por vía oral
    Para el grupo de Atezo+TCZ durante la fase 1
    Enfermedades desmielinizantes del sistema nervioso central o trastornos convulsivos preexistentes
    Ant de diverticulitis o diverticulosis que precise de tratamiento antibiótico u otras afecciones sintomáticas del tubo digestivo bajo que puedan predisponer a sufrir perforaciones
    Enfermedad hepática actual no relacionada con el diagnóstico de cáncer subyacente
    TB activa que precise de tratamiento en los 3 años anteriores al momento basal
    TB latente no tratada
    Inmunodeficiencia primaria o secundaria
    E.5 End points
    E.5.1Primary end point(s)
    1. Objective response rate
    1. Tasa de respuesta objetiva
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to 5 years
    Hasta 5 años
    E.5.2Secondary end point(s)
    1. Progression-free survival
    2. Overall survival after randomization
    3. Overall survival rate at specific time points
    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
    8. Change from baseline in targeted clinical laboratory test results
    9. Plasma or serum concentration of each drug at specified time points
    10. For drugs for which anti-drug antibody (ADA) formation is measured: presence of ADAs during the study relative to the presence of ADAs at baseline
    . Supervivencia libre de progresión
    2. Supervivencia global después de la aleatorización
    3. Tasa global de supervivencia en puntos temporales específicos
    4. Duración de la respuesta.
    5. Control de enfermedades.
    6. Incidencia, naturaleza y gravedad de los eventos adversos y anomalías de laboratorio, con la gravedad determinada de acuerdo con los Criterios de Terminología Comunes para Eventos Adversos del National Cancer Institute, Versión 4.0
    7. Cambio desde el inicio en signos vitales.
    8. Cambio desde el inicio en los resultados de las pruebas de laboratorio clínico dirigidas.
    9. Concentración en plasma o suero de cada medicamento en puntos de tiempo específicos
    10. Para los medicamentos para los que se mide la formación de anticuerpos antidrogas (ADA): presencia de ADA durante el estudio en relación con la presencia de ADA al inicio del estudio
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-2. Up to 5 years
    3. 12 months
    4-8. Up to 5 years
    9-10. Atezo Control Arm and Atezo-EV Arm (Preliminary Phase): Day (D) 1 of Cycle (C) 1, 2, 4, 8, 12, 16 and treatment discontinuation (TD) visit
    Atezo + Nira and Atezo + Isa Arm (Preliminary Phase): D1 of C1, 2, 4, 6, 8, 10, 12, 16; TD visit
    Atezo + Hu5F9-G4 Arm: D1, 8, 22 of C1; D1 of C2, 4, 8, 12, 16; TD visit
    Atezo + Isa Arm (Expansion Phase): D1, 8, 15 of C1; D1 of C2, 3, 4, 6, 8, 10, 12, 16; TD visit
    Atezo + Nira(Expansion Phase) and Atezo + Lina Arm: D1, 15 of C1; Day 1 of C2, 4, 8, 12, 16; TD visit
    Atezo + TCZ Arm: D1 of C1, 2, 4, 6, 8, 10, 12, 14, 16; every fourth cycle after cycle 16; TD visit
    Atezo-EV Arm (Expansion Phase): D1, 8 of C1, D1 of C2, 4, 8, 12, 16 TD visit
    1-2. Hasta 5 años
    3. 12 meses
    4-8. Hasta 5 años
    9-10. Brazo de control de Atezo y brazo de Atezo-EV (fase preliminar): día (D) 1 del ciclo (C) 1, 2, 4, 8, 12, 16 y visita de interrupción del tratamiento (TD)
    Atezo + Nira y Atezo + Isa Arm (fase preliminar): D1 de C1, 2, 4, 6, 8, 10, 12, 16; TD visita
    Atezo + Hu5F9-G4 Brazo: D1, 8, 22 de C1; D1 de C2, 4, 8, 12, 16; TD visita
    Atezo + Isa Arm (fase de expansión): D1, 8, 15 de C1; D1 de C2, 3, 4, 6, 8, 10, 12, 16; TD visita
    Atezo + Nira (fase de expansión) y Atezo + Lina Arm: D1, 15 de C1; Día 1 de C2, 4, 8, 12, 16; TD visita
    Atezo + TCZ Brazo: D1 de C1, 2, 4, 6, 8, 10, 12, 14, 16; cada cuarto ciclo después del ciclo 16; TD visita
    Brazo Atezo-EV (Fase de expansión): D1, 8 de C1, D1 de C2, 4, 8, 12, 16 TD visita
    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 Yes
    E.6.13.1Other scope of the trial description
    immunogenicity
    inmunogenicidad
    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 Yes
    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 trial7
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Korea, Republic of
    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
    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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 92
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 213
    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 state64
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 230
    F.4.2.2In the whole clinical trial 305
    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)
    Patients may continue to receive atezolizumab as part of an extension study. Currently, the Sponsor does not have any plans to provide post-study access to atezolizumab or any other study treatments or interventions to patients who do not qualify for the extension study
    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 Decision2019-04-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-25
    P. End of Trial
    P.End of Trial StatusOngoing
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