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    Summary
    EudraCT Number:2021-001975-17
    Sponsor's Protocol Code Number:N/A
    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:2021-11-19
    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 number2021-001975-17
    A.3Full title of the trial
    A randomised phase II study comparing 3 vs 6 cycles of platinum-based chemotherapy prior to maintenance avelumab in advanced urothelial cancer
    Estudio de fase II aleatorizado para comparar 3 y 6 ciclos de quimioterapia con un derivado del platino antes del tratamiento de mantenimiento con avelumab en el cáncer urotelial avanzado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    3 or 6 cycles of platinum-based chemotherapy prior to maintenance avelumab for bladder cancer
    3 ó 6 ciclos de quimioterapia basada en platino antes del mantenimiento con avelumab para el cáncer de vejiga
    A.3.2Name or abbreviated title of the trial where available
    DISCUS
    DISCUS
    A.4.1Sponsor's protocol code numberN/A
    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 SponsorQueen Mary University of London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Healthcare KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQueen Mary University of London
    B.5.2Functional name of contact pointThomas Powles
    B.5.3 Address:
    B.5.3.1Street AddressCentre for Experimental Cancer Medicine, Old Anatomy Building, Charterhouse Square
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeEC1M 6BQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44(0) 20 7882 8489
    B.5.5Fax number+44(0) 20 7882 8490
    B.5.6E-mailBCI-DISCUS@qmul.ac.uk
    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 Avelumab (Bavencio)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Europe 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 nameAvelumab (Bavencio)
    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 INNAvelumab
    D.3.9.1CAS number 1537032-82-8
    D.3.9.3Other descriptive nameMSB0010718C
    D.3.9.4EV Substance CodeAS1
    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: 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 Cisplatin
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCisplatin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCisplatin
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 Gemcitabine
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGemcitabine
    D.3.4Pharmaceutical form Powder for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGemcitabine hydrochloride
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP 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 Carboplatin
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCarboplatin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCarboplatin
    D.3.9.1CAS number 41575-94-4
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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
    Unresectable locally advanced or metastatic urothelial carcinoma
    Carcinoma urotelial localmente avanzado irresecable o metastásico, confirmado histológicamente, sin tratamiento previo
    E.1.1.1Medical condition in easily understood language
    Cancer in the cells that line the bladder or metastatic bladder cancer
    Cáncer en las células que recubren la vejiga o cáncer de vejiga metastásico
    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 10046714
    E.1.2Term Urothelial carcinoma bladder
    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 effect of 3 vs 6 cycles platinum-based, front line chemotherapy followed by maintenance avelumab based on patient-reported outcomes (PROs) in the study population.
    Evaluar el efecto de 3 y 6 ciclos de quimioterapia de primera línea con un derivado del platino, seguidos de mantenimiento con avelumab, basándose en los resultados comunicados por los pacientes
    (RCP) en la población del estudio.
    E.2.2Secondary objectives of the trial
    1. To evaluate the effect of 3 vs 6 cycles platinum-based, front line chemotherapy followed by maintenance avelumab based on additional patient-reported outcomes (PROs) in the study population.

    2. To evaluate the effect of 3 vs 6 cycles platinum-based, front line chemotherapy followed by maintenance avelumab based on clinician reported outcomes.

    3. To evaluate the safety and tolerability of 3 vs 6 cycles of platinum-based, front line chemotherapy followed by maintenance avelumab therapy.

    4. To assess the efficacy of 3 vs 6 cycles platinum based, front line chemotherapy followed by maintenance avelumab in patients with advanced UC.
    1. Evaluar el efecto de 3 y 6 ciclos de quimioterapia de primera línea con un derivado del platino, seguidos de mantenimiento con avelumab, basándose en otros resultados comunicados por los pacientes (RCP) en la población del estudio.

    2. Evaluar el efecto de 3 y 6 ciclos de quimioterapia de primera línea con un derivado del platino, seguidos de mantenimiento con avelumab, basándose en los resultados comunicados por el médico.

    3. Evaluar la seguridad y tolerabilidad de 3 y 6 ciclos de quimioterapia de primera línea con un derivado del platino, seguidos de tratamiento mantenimiento con avelumab.

    4. Evaluar la eficacia de 3 y 6 ciclos de quimioterapia de primera línea con un derivado del platino, seguidos de mantenimiento con avelumab, en pacientes con CU avanzado.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing and able to provide written informed consent.

    2. Ability to comply with the protocol, including but not limited to, the repeated completion of the EORTC QLQ-C30 questionnaires.

    3. Age ≥ 18 years.

    4. Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous or sarcomatoid differentiation or mixed cell types are eligible but a component of urothelial cancer is required.

    5. Measurable disease by RECIST v1.1.

    6. Eligible for gemcitabine/ cisplatin or gemcitabine/carboplatin. The following criteria are established for the use of carboplatin (patients not fulfilling the following carboplatin criteria should be considered for gemcitabine/ cisplatin):

    a. GFR <60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault formula. Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgement.

    b. ECOG or WHO performance status of 2.

    c. NCI CTCAE Grade ≥2 audiometric hearing loss.

    d. NYHA Class III heart failure.

    7. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.

    8. Adequate haematologic and organ function as defined below:

    a. Haemoglobin ≥ 9.0g/dL

    b. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500/µL) without growth factor support

    c. Platelet count ≥ 100 x 109 /L (≥100,000/µL)

    d. Total serum bilirubin ≤1.5 x institutional upper limit of normal (ULN) (this will not apply to subjects with confirmed Gilbert’s syndrome [persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology], who will be allowed only in consultation with their physician.

    e. Serum transaminases (AST/ALT) ≤2.5 x the institutional ULN with the following exception in patients with documented liver metastases: AST and/or ALT ≤5 × ULN

    f. GFR ≥30mL/min measured by Cockroft-Gault.

    9. Negative serum or urine pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential only. Non-childbearing potential is defined as either:

    a. Postmenopausal ≥ 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments OR

    b. Documented irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR

    c. <50 years of age who have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels within local institution postmenopausal ranges.

    10. Agreement to use adequate contraceptive measures (Refer to section 11.30 for full details).
    1. Disposición y capacidad para otorgar el consentimiento informado por escrito.

    2. Capacidad para cumplir el protocolo, entre otros, cumplimentación repetida de los cuestionarios QLQ-C30 de la EORTC.

    3. Edad ≥18 años.

    4. Carcinoma urotelial localmente avanzado irresecable o metastásico, confirmado histológicamente (es decir, cáncer de vejiga, pelvis renal, uréter o uretra). Podrán participar pacientes con diferenciación epidermoide o sarcomatoide o con tipos celulares mixtos, pero es obligatorio un componente de cáncer urotelial.

    5. Enfermedad mensurable conforme a los criterios RECIST v1.1.

    6. Idoneidad para recibir gemcitabina/cisplatino o gemcitabina/carboplatino. Se establecen los
    siguientes criterios para el uso de carboplatino (si el paciente no cumple los siguientes criterios
    para recibir carboplatino, debe considerarse el uso de gemcitabina/cisplatino):

    a. FG <60 ml/min pero ≥30 ml/min (medida con la fórmula de CockcroftGault). Los sujetos con una FG ≥50 ml/min y que no cumplan ningún otro criterio de elegibilidad para recibir cisplatino podrán ser considerados aptos para el tratamiento con cisplatino según el criterio clínico del investigador.
    b. Estado funcional del ECOG o de la OMS de 2.
    c. Hipoacusia audiométrica de grado ≥2 según los CTCAE del NCI.
    d. Insuficiencia cardíaca de clase III de la NYHA.

    7. Estado funcional de 0, 1 o 2 según el Eastern Cooperative Oncology Group (ECOG).

    8. Función hematológica y orgánica adecuada determinada por los parámetros siguientes:

    a. Hemoglobina ≥9 g/dl.
    b. Recuento absoluto de neutrófilos (RAN) ≥1,5 x 109/l (≥1500/µl) sin apoyo con factores decrecimiento.
    c. Recuento de linfocitos ≥100 x 109/l (≥100 000/µl).
    d. Bilirrubina sérica total ≤1,5 veces el límite superior de la normalidad (LSN) del centro (no se aplicará a los sujetos con síndrome de Gilbert confirmado [hiperbilirrubinemia persistente o recurrente predominantemente no conjugada en ausencia de hemólisis o hepatopatía], que solo podrán ser incluidos tras consultar con su médico).
    e. Transaminasas séricas (AST/ALT) ≤2,5 veces el LSN del centro, con la siguiente excepción en los pacientes con metástasis hepáticas documentadas: AST o ALT ≤5 veces el LSN.
    f. FG ≥30 ml/min medida con la fórmula de Cockroft-Gault.

    9. Prueba de embarazo en suero u orina negativa en las 2 semanas previas al día 1 del ciclo 1 únicamente en las mujeres sin capacidad reproductiva. Las mujeres sin capacidad reproductiva son las que presentan:

    a. Posmenopausia, edad ≥50 años y amenorrea durante al menos 12 meses después de la suspensión de todos los tratamientos hormonales exógenos O
    b. Documentación de esterilización quirúrgica irreversible por histerectomía, ovariectomía bilateral o
    salpingectomía bilateral, pero no por ligadura de trompas O
    c. Edad inferior a 50 años y presencia de amenorrea durante 12 meses o más tras la interrupción de los tratamientos hormonales exógenos y con concentraciones de LH y FSH dentro de los intervalos posmenopáusicos de cada centro.

    10. Compromiso de utilizar métodos anticonceptivos adecuados (véanse todos los detalles en la sección 11.30).
    E.4Principal exclusion criteria
    1. Prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC.
    2. Prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: a platinum containing regimen (cisplatin or carboplatin) in the neoadjuvant or adjuvant setting if more than 6 months since last cycle have occurred.
    3. Pregnant and lactating female patients
    4. Known history of active CNS metastases. Patients with treated CNS metastases are permitted on the study if all of the following are true:
    a. CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis
    b. the subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks prior to C1D1 (if requiring steroid treatment)
    c. subject does not have leptomeningeal disease
    5. Prior allogeneic stem cell or solid organ transplantation
    6. Oral or IV steroids for 14 days prior to C1D1. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed. Patients receiving treatment for CNS metastases at a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks prior to screening are eligible.
    7. Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study
    8. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment
    9. Concurrent treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment
    10. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
    11. Malignancies other than urothelial carcinoma of the bladder within 3 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive)
    12. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction or cerebral vascular accident/stroke within 6 months prior to enrolment, unstable arrhythmias, or unstable angina
    13. Radiotherapy within 2 weeks prior to C1D1. Patients must have recovered adequately from toxicities resulting from the intervention prior to starting study treatment
    14. Major surgery (defined as requiring general anaesthesia and >24-hour inpatient hospitalization) within 4 weeks prior to randomisation. Patients must have recovered adequately from complications from the intervention prior to starting study treatment.
    15. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted)
    16. Active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.
    17. Positive HIV test
    18. Active tuberculosis
    19. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
    20. History of autoimmune-related hypothyroidism, unless on a stable dose of thyroid replacement hormone
    21. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies
    22. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of avelumab
    23. Active infection requiring systemic therapy
    ..................
    1. Tratamiento previo con un inhibidor de PD-(L)-1 por cualquier neoplasia maligna, incluido el CU en estadio inicial. 2. Tratamiento sistémico previo para el carcinoma urotelial localmente avanzado o metastásico con las siguientes excepciones: derivado del platino (cisplatino o carboplatino) en el contexto neoadyuvante o adyuvante si han transcurrido más de 6 meses desde el últimociclo. 3.Mujeres embarazadas y lactantes. 4. Antecedentes conocidos de metástasis activas en el SNC. Los pacientes con metástasis en el SNC tratadas podrán participar en el estudio si se cumplen todas las condiciones siguientes: a. Las metástasis en el SNC se han mantenido clínicamente estables durante al menos 4 semanas antes de la selección y las exploraciones basales no muestran signos de metástasis nuevas o que hayan aumentado de tamaño. b. El sujeto ha recibido una dosis estable ≤10 mg/día de prednisona o equivalente durante al menos 2 semanas antes del D1C1 (si necesita tratamiento con esteroides). c. El sujeto no presenta enfermedad leptomeníngea. 5. Alotrasplante de células progenitoras o trasplante de órgano sólido previo. 6. Esteroides orales o IV durante 14 días antes del D1C1. Se permite el uso de corticosteroides inhalados, dosis de reposición fisiológica de glucocorticoides (es decir, por insuficiencia suprarrenal) y mineralocorticoides (p. ej., fludrocortisona). Podrán participar pacientes que hayan recibido tratamiento para metástasis en el SNC en una dosis estable ≤10 mg/día de prednisona o equivalente durante al menos 2 semanas antes de la selección.
    7. Administración de una vacuna de microbios vivos atenuados en las 4 semanas previas a la
    inclusión o previsión de que dicha vacuna sea necesaria durante el estudio 8. Tratamiento con inmunoestimuladores sistémicos (entre otros, interferones o interleucina [IL-2) en las 4 semanas previas a la inclusión o durante cinco semividas del fármaco, lo que suponga menos tiempo (véase la sección 11.26). 9. Tratamiento concomitante con cualquier otro fármaco en investigación o participación en otro ensayo clínico con fines terapéuticos en las 4 semanas previas a la inclusión. 10. Signos de enfermedad concomitante significativa no controlada que podría afectar al cumplimiento del protocolo o la interpretación de los resultados, como enfermedades hepáticas importantes (cirrosis, trastornos convulsivos significativos no controlados o síndrome de la vena cava superior)
    11. Neoplasias malignas distintas del carcinoma urotelial de vejiga en los 3 años previos al día 1 del ciclo 1, a excepción de aquellas con un riesgo insignificante de metástasis o muerte y tratadas con un resultado curativo previsto (como carcinoma in situ del cuello uterino tratado adecuadamente, cáncer basocelular o espinocelular de la piel, o carcinoma ductal in situ tratado quirúrgicamente con intención curativa) o cáncer de próstata localizado tratado con intención curativa y ausencia de
    recidiva del antígeno prostático específico (PSA) o cáncer de próstata menor (puntuación de Gleason ≤3 + 4 y PSA <10 ng/ml sometido a vigilancia activa y no tratado previamente). 12. Enfermedad cardiovascular importante, como cardiopatía de clase II o superior de la New York Heart Association, infarto de miocardio o accidente cerebrovascular/ictus en los 6 meses previos a la inclusión, arritmias inestables o angina inestable.13. Radioterapia en las 2 semanas previas al D1C1. Los pacientes deberán haberse recuperado debidamente de las toxicidades derivadas de la intervención antes de empezar el tratamiento del estudio. 14. Cirugía mayor (definida como la necesidad de anestesia general y de hospitalización durante más de 24 horas) en las 4 semanas previas a la aleatorización. Los pacientes deberán haberse recuperado debidamente de las complicaciones de la intervención antes de empezar el tratamiento del estudio. 15. Antecedentes de fibrosis pulmonar idiopática (incluida neumonitis), neumonitis de origen medicamentoso, neumonía organizada (es decir, bronquiolitis obliterante, neumonía organizada criptógena) o signos de neumonitis activa en la TC de tórax realizada en la selección (se permiten los antecedentes de neumonitis por radiación en el campo irradiado (fibrosis)). 16. Hepatitis activa (definida como un resultado positivo en el análisis del antígeno de superficie del virus de la hepatitis B [HBsAg] en la selección) o hepatitis C. Podrán participar pacientes con infección pasada por el virus de la hepatitis B (VHB) o infección por el VHB resuelta (definida por un resultado negativo en un análisis del HBsAg y la presencia de anticuerpos contra el antígeno central del virus de la hepatitis B [anti-HBc]). 17. Prueba de VIH positiva. 18. Tuberculosis activa. 19. Antecedentes de enfermedades autoinmunitarias, entre ellas, miastenia grave, miositis, hepatitis autoinmunitaria, lupus eritematoso sistémico, artritis reumatoide,
    enfermedad inflamatoria intestinal, trombosis vascular asociada a síndrome................
    E.5 End points
    E.5.1Primary end point(s)
    Change in GHS/QoL scale scores from baseline to completion of 6 cycles of treatment. Patients who withdraw from treatment between Cycles 4 and 6 will be included, provided an EORTC QLQ-C30 questionnaire is completed within 14 days after the date of withdrawal.
    Cambio en las puntuaciones de la escala GHS/QoL desde el inicio hasta la finalización de 6 ciclos de tratamiento. Se incluirán los pacientes que abandonen el tratamiento entre los ciclos 4 y 6, siempre que se complete un cuestionario EORTC QLQ-C30 en los 14 días siguientes a la fecha de abandono.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patient reported outcomes reported at completion of cycle 6. Patients who withdraw from treatment between Cycles 4 and 6 will be included, provided an EORTC QLQ-C30 questionnaire is completed within 14 days after the date of withdrawal.
    Resultados comunicados por los pacientes al finalizar el ciclo 6. Se incluirán los pacientes que abandonen el tratamiento entre los ciclos 4 y 6, siempre que se complete un cuestionario EORTC QLQ-C30 en los 14 días siguientes a la fecha de abandono.
    E.5.2Secondary end point(s)
    1.Quality of Life assessment from baseline to the completion of 10 Cycles of treatment using the GHS/QOL scale score, as per the primary endpoint methodology.

    2.Quality of Life assessment from the beginning of cycle 5 to the completion of 10 Cycles of treatment using the GHS/QOL scale score, as per the primary endpoint methodology.

    3.Change in GHS/QOL scale scores from baseline to the end of assessment (wk54), as per the primary endpoint methodology.

    4.The above endpoints will be repeated using the EORTC QLQ-C30 scale score.

    5.GHS/QoL scale score time to deterioration (TTD), where deterioration in the GHS/QoL scale score is defined as a decrease by ≥10 points at any time point after baseline with no subsequent observations with a <10 point decrease from baseline.

    6.Change in the GHS/QOL scale score from baseline as per the primary endpoint, but adjusted for baseline imbalances in GHS/QOL scale scores.

    7. Performance status as measured by the Karnofsky Scale on completion of 6 cycles of treatment.

    8. Incidence, nature and severity of adverse events graded according to NCI-CTCAE v5.0 at the following timepoints:
    a. Throughout treatment
    b. On completion of Cycle 6 of treatment
    c. Between Cycle 4 and the completion of Cycle 10.

    9. Treatment discontinuation rate due to AEs.

    10. Overall response rate in each randomised treatment arm defined as the proportion of patients who achieved complete response (CR) or partial response (PR) according to RECIST v1.1 recorded from randomisation until week 20. (investigator assessed unconfirmed best response)

    11. Progression free survival rate at 20 weeks post randomisation (PFS rate) in each treatment arm defined as the proportion of patients who did not experience disease progression or death from any cause according to RECIST v1.1 recorded from randomisation until week 20.

    12. Duration of response defined as the time from first documentation of CR or PR to disease progression (RECIST v1.1) or death from any cause, whichever occurs first.

    13. Overall survival (OS), defined as the time between the date of randomisation and death due to any cause.
    1. Evaluación de la calidad de vida desde el inicio hasta la finalización de los 10 ciclos de tratamiento utilizando la puntuación de la escala GHS/QOL, según la metodología del criterio de valoración primario.

    2. Evaluación de la calidad de vida desde el inicio del ciclo 5 hasta la finalización de los 10 ciclos de tratamiento utilizando la puntuación de la escala GHS/QOL, según la metodología del criterio de valoración primario.

    3.Cambio en las puntuaciones de la escala GHS/QOL desde el inicio hasta el final de la evaluación (semana 54), según la metodología de los criterios de valoración primarios.

    4.Los criterios de valoración anteriores se repetirán utilizando la puntuación de la escala EORTC QLQ-C30.

    5.Tiempo de deterioro de la puntuación de la escala GHS/QoL (TTD), donde el deterioro de la puntuación de la escala GHS/QoL se define como una disminución de ≥10 puntos en cualquier punto de tiempo después de la línea de base, sin observaciones posteriores con una disminución de <10 puntos desde la línea de base.

    6.Cambio en la puntuación de la escala GHS/QoL desde el punto de partida, según el criterio de valoración primario, pero ajustado por los desequilibrios basales en las puntuaciones de la escala GHS/QoL.

    7. Estado de rendimiento medido por la escala de Karnofsky al finalizar los 6 ciclos de tratamiento.

    8. Incidencia, naturaleza y gravedad de los acontecimientos adversos calificados según el NCI-CTCAE v5.0 en los siguientes puntos temporales:
    a. A lo largo del tratamiento
    b. Al finalizar el ciclo 6 de tratamiento
    c. Entre el ciclo 4 y la finalización del ciclo 10.

    9. Tasa de interrupción del tratamiento debido a EA.

    10. Tasa de respuesta global en cada brazo de tratamiento aleatorizado, definida como la proporción de pacientes que lograron una respuesta completa (RC) o una respuesta parcial (RP) según RECIST v1.1 registrada desde la aleatorización hasta la semana 20. (mejor respuesta no confirmada evaluada por el investigador)

    11. Tasa de supervivencia libre de progresión a las 20 semanas después de la aleatorización (tasa de SLP) en cada brazo de tratamiento definida como la proporción de pacientes que no experimentaron progresión de la enfermedad o muerte por cualquier causa según RECIST v1.1 registrada desde la aleatorización hasta la semana 20.

    12. Duración de la respuesta definida como el tiempo transcurrido desde la primera documentación de RC o RP hasta la progresión de la enfermedad (RECIST v1.1) o la muerte por cualquier causa, lo que ocurra primero.

    13. Supervivencia global (SG), definida como el tiempo transcurrido entre la fecha de aleatorización y la muerte por cualquier causa.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.From baseline to the completion of 10 Cycles of treatment
    2.From the beginning of cycle 5 to the completion of 10 Cycles of treatment
    3.Baseline to the end of assessment (wk54)
    4.As per timepoints in endpoints 1 - 3
    5.From baseline until a decrease by ≥10 points at any time point after baseline with no subsequent observations with a <10 point decrease from baseline
    6. From baseline as per the primary endpoint
    7. Upon completion of 6 cycles of treatment
    8a. Throughout treatment
    8b. Upon completion of 6 cycles of treatment
    8c. Between Cycle 4 and the completion of Cycle 10
    9. Enrolment until 90 day safety visit
    10. From randomisation until week 20
    11. From randomisation until week 20
    12. Enrolment until death due to any cause
    13. From randomisation until death
    1Desde visita basal hasta la finalización de 10 Ciclos
    2Desde el inicio del ciclo 5 hasta la finalización de los 10 ciclos
    3Desde visita basal hasta el final de la evaluación (semana 54)
    4Según en los tiempos definidos en las variables de 1 a 3
    5Desde la visita basal hasta una disminución de ≥10 puntos sin observaciones posteriores con una disminución de <10 puntos desde la línea de base
    6A partir del punto de referencia
    7Al finalizar los 6 ciclos
    8aEn el tratamiento
    8bAl finalizar los 6 ciclos
    8cEntre el ciclo 4 y la finalización del ciclo 10
    9Inscripción hasta la visita de seguridad de 90 días
    10Desde la aleatorización hasta la semana 20
    11Desde la aleatorización hasta la semana 20
    12Inscripción hasta la muerte por cualquier causa
    13Desde la aleatorización hasta la muer
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 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 concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of trial is defined as last patient last visit.
    El fin de ensayo se define como la última visita del último paciente.
    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 months2
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 179
    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 state114
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 224
    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)
    Upon completion of study treatment, patients will be treated at the discretion of the treating investigator in line with local standard of care polices. Patients deriving benefit on completion of 2 years of treatment with avelumab can be switched to locally supplied avelumab sourced via the site's local processes at the discretion of the treating investigator.
    Una vez finalizado el tratamiento del estudio, los pacientes serán tratados según la práctica clínica habitual del centro. Los pacientes que obtengan beneficios al finalizar los 2 años de tratamiento con avelumab podrán cambiar a avelumab suministrado localmente a través la práctica clínica habitual del centro.
    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 Decision2022-03-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-02-23
    P. End of Trial
    P.End of Trial StatusOngoing
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