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    Summary
    EudraCT Number:2019-004023-20
    Sponsor's Protocol Code Number:MK-3475-992
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-22
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-004023-20
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Placebo-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) versus CRT Alone in Participants with Muscle-invasive Bladder Cancer (MIBC) (KEYNOTE-992)
    Studio clinico di fase 3, randomizzato, in doppio cieco, controllato con placebo per studiare l’efficacia e la sicurezza di Pembrolizumab (MK-3475) in combinazione con la Chemioradioterapia (CRT) versus la sola Chemioradioterapia in soggetti con tumore alla vescica muscolo-invasivo (MIBC) (KEYNOTE-992)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chemoradiotherapy +/- pembrolizumab in participants with MIBC
    Chemioradioterapia +/- pembrolizumab in partecipanti con MIBC
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberMK-3475-992
    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 SponsorMERCK SHARP & DOHME CORP. UNA SUSSIDIARIA DI MERCK & CO. INC.
    B.1.3.4CountryUnited States
    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 supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. B
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMSD Italia
    B.5.2Functional name of contact pointDivisione Ricerca Clinica
    B.5.3 Address:
    B.5.3.1Street AddressVia Vitorchiano 151
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00189
    B.5.3.4CountryItaly
    B.5.4Telephone number00390636191371
    B.5.5Fax number00390636380371
    B.5.6E-mailgcto.italy@merck.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 namePembrolizumab
    D.3.2Product code [MK-3475]
    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 INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 KEYTRUDA (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme 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 name-
    D.3.2Product code [-]
    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 INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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 Cisplatino
    D.2.1.1.2Name of the Marketing Authorisation holder-
    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 nameCisplatino
    D.3.2Product code [-]
    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 INNCISPLATINO
    D.3.9.1CAS number 15663-27-1
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive name-
    D.3.9.4EV Substance Code-
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Gemcitabina
    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 nameGemcitabina
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Powder 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 INNGEMCITABINA
    D.3.9.1CAS number 95058-81-4
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive name-
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name Fluorouracile
    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 nameFluorouracile
    D.3.2Product code [-]
    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 INNFLUOROURACILE
    D.3.9.1CAS number 51-21-8
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name Mitomicina C
    D.2.1.1.2Name of the Marketing Authorisation holder-
    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 nameMitomicina C
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Powder for 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 INNMITOMICINA
    D.3.9.1CAS number 50-07-7
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Muscle Invasive Bladder Cancer
    tumore alla vescica muscolo-invasivo
    E.1.1.1Medical condition in easily understood language
    Patients with Muscle Invasive Bladder Cancer
    pazienti con tumore alla vescica muscolo-invasivo
    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 PT
    E.1.2Classification code 10005003
    E.1.2Term Bladder cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10022877
    E.1.2Term Invasive bladder cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To compare bladder intact event-free survival in participants from Arm A (pembrolizumab + chemoradiotherapy) and Arm B (placebo + chemoradiotherapy), based on cystoscopy, biopsy with central pathology review (if applicable), urine cytology and radiographic assessment by blinded independent central review.
    1. Confrontare la sopravvivenza libera da eventi, con vescica intatta, nei partecipanti del braccio A (pembrolizumab + chemioradioterapia) e del braccio B (placebo + chemioradioterapia), in base a cistoscopia, biopsia con valutazione patologica centralizzata (ove applicabile), citologia urinaria e valutazione radiografica mediante revisione centrale indipendente in cieco.
    E.2.2Secondary objectives of the trial
    1. To compare overall survival between Arm A (pembrolizumab + chemoradiotherapy) and Arm B (placebo + chemoradiotherapy).
    2. To evaluate rate of metastasis-free survival.
    3. To evaluate time to occurrence of non–muscle-invasive bladder cancer (NMIBC).
    4. To evaluate the safety and tolerability of pembrolizumab + chemoradiotherapy.
    5. To evaluate changes from baseline in health-related quality of life and time to deterioration, using 2 general instruments (European Organization for Research and Treatment of Cancer [EORTC] QoL questionnaire-Core 30 [QLQ-
    C30], and European Quality of Life [EuroQoL]-5 Dimensions, 5-level Questionnaire [EQ-5D-5L]) and one disease-specific instrument (Bladder Cancer Index [BCI]).
    6. To evaluate time to cystectomy.
    1. Confrontare la sopravvivenza globale tra il Braccio A (pembrolizumab + chemioradioterapia ) e il Braccio B (placebo + chemioradioterapia ).
    2. Valutare il tasso di sopravvivenza libera da metastasi.
    3. Valutare il tempo alla prima occorrenza di NMIBC.
    4. Valutare la sicurezza e la tollerabilità di pembrolizumab + chemioradioterapia.
    5. Valutare le variazioni rispetto al basale della qualità della vita correlata alla salute e del tempo al deterioramento, utilizzando 2 strumenti generali (questionario EORTC [European Organisation for Research and Treatment of Cancer] QLQ-C30 [QoL-Core 30], e questionario EQ-5D-5L [European Quality of Life [EuroQoL]-5 Dimensions, 5level]) e uno strumento specifico per la malattia (BCI [Bladder Cancer Index]).
    6.Valutare il tempo alla cistectomia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Has a histologically confirmed diagnosis of MIBC with predominant urothelial histology (histology and presence of muscle invasion to be confirmed by BICR) obtained via a diagnostic or maximal TURBT performed within 60 days prior to enrollment (signing of
    ICF).
    2. Has clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT of the chest and CTU/MRU of abdomen and pelvis), confirmed by BICR.
    3. Has provided tumor specimen to the central vendor to determine PDL1 status prior to randomization.
    4. Has planned and is eligible to receive CRT and one of the protocolspecified radiosensitizing chemotherapy regimens.
    5. Has an ECOG performance status of 0,1, or 2 assessed within 14 days prior to randomization.
    6. Demonstrates adequate organ function. All screening laboratory tests should be performed within 14 days prior to randomization.
    7. Is male or female, at least 18 years of age, at the time of signing the informed consent.
    8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of study intervention. • Refrain from donating sperm PLUS either: • Be abstinent from heterosexual intercourse as
    their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below: - Agree
    to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
    9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: - Is not a WOCBP OR - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per
    year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 180 days after the last dose of study intervention
    and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in
    relationship to the first dose of study intervention. - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention. - If a urine test cannot be confirmed
    as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, theparticipant must be excluded from participation if the serum pregnancy result is positive. - The investigator is responsible for review of medical history, menstrual
    history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    10.The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main
    study without participating in future biomedical research.
    1. Ha una diagnosi confermata istologicamente di MIBC con componente uroteliale predominante (istologia e presenza di invasione muscolare devono essere confermate mediante BICR) ottenuta tramite TURBT diagnostica o massimale eseguita nei 60 giorni precedenti l’arruolamento (firma del modulo di consenso informato).
    2. È affetto/a da carcinoma della vescica clinicamente non metastatico (N0M0) rilevato con imaging (TC toracica e CTU/MRU di addome e pelvi), confermato mediante BICR.
    3. Ha consegnato un campione tumorale al laboratorio centralizzato per determinare lo stato di PD-L1 prima della randomizzazione.
    4. Ha pianificato ed è idoneo/a a ricevere CRT e uno dei regimi chemioterapici radiosensibilizzanti specificati nel protocollo.
    5. Ha un performance status ECOG pari a 0, 1 o 2, valutato nei 14 gg precedenti la randomizzazione.
    6. Dimostra funzionalità d’organo adeguata. Tutti i test di laboratorio di screening devono essere eseguiti nei 14 giorni precedenti la randomizzazione.
    7. È un soggetto di sesso maschile o femminile di età pari o superiore a 18 anni al momento della firma del consenso informato.
    8. I pazienti di sesso maschile sono idonei a partecipare se acconsentono a quanto segue durante il periodo di trattamento sperimentale e per almeno 180 giorni dopo l’ultima somministrazione di farmaco sperimentale.
    • Astenersi dal donare sperma
    PIÙ:
    • Non avere rapporti eterosessuali come stile di vita preferito e abituale (astinenza a lungo termine e persistente) e accettare di astenersi da tali rapporti
    OPPURE
    • Acconsentire a utilizzare un metodo contraccettivo, a meno che non sia confermata l’azoospermia (in seguito a vasectomia o secondaria a cause mediche) come specificato di seguito:
    ¿ Acconsentire a utilizzare un preservativo maschile più utilizzo da parte della partner di un metodo contraccettivo aggiuntivo in caso di rapporti sessuali penetrativi vaginali con una donna in età fertile che non è al momento incinta.
    9. Le pazienti di sesso femminile sono idonee alla partecipazione se non sono in gravidanza o in allattamento, e se almeno una delle condizioni indicate di seguito risulta applicabile:
    - Non sono donne in età fertile
    OPPURE
    - Sono donne in età fertile che utilizzano un metodo contraccettivo altamente efficace (con un tasso di insuccesso <1% l’anno), con scarsa dipendenza dell’utilizzatore, o che non hanno rapporti eterosessuali come stile di vita preferito e abituale (astinenza a lungo termine e persistente) durante il periodo di intervento e per almeno 180 giorni dopo l’ultima dose del farmaco sperimentale, e che acconsentono a non donare ovuli ad altri né a congelarli/conservarli per uso personale a scopo riproduttivo durante questo periodo. Lo sperimentatore deve valutare la possibilità di fallimento del metodo contraccettivo (mancata compliance, iniziato di recente) in relazione alla prima dose del trattamento sperimentale.
    - Le donne in età fertile devono avere esito negativo al test di gravidanza ad alta sensibilità (eseguito su urine o siero secondo quanto stabilito dai regolamenti locali) nelle 24 ore che precedono la prima dose del trattamento sperimentale.
    - Se non può essere confermata la negatività del test sulle urine (ad es. risultato ambiguo), è necessario eseguire un test di gravidanza su siero. In tale caso, la paziente deve essere esclusa dalla partecipazione se il test di gravidanza su siero risulta positivo.
    - Lo sperimentatore è responsabile dell’analisi dell’anamnesi medica, di quella mestruale e dell’attività sessuale recente per ridurre il rischio di inclusione nello studio di una donna in gravidanza allo stadio iniziale non rilevata.
    10. Il partecipante (o il rappresentante legalmente riconosciuto, ove applicabile) fornisce il consenso/assenso informato scritto per lo studio. Il partecipante deve inoltre fornire il consenso/assenso a partecipare a future ricerche biomediche. Tuttavia, il soggetto può partecipare allo studio principale senza partecipare a future ricerche biomediche.
    E.4Principal exclusion criteria
    1. Has the presence of diffuse CIS (multiple foci of CIS) throughout the bladder. 2. Has the presence of UC at any site outside of the urinary bladder in the previous 2 years except for Ta/T1/CIS of the upper tract if the patient has undergone a complete nephroureterectomy. 3. Has the presence of any small cell or neuroendocrine component in the tumor tissue sample. 4. Has a known additional malignancy that is progressing or has required active therapy within the past 3 years. 5. Has the presence of bilateral hydronephrosis during the Screening period. 6. Has limited bladder function with frequency of small amounts of urine (< 30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter. 7. Has received prior pelvic/local radiation therapy or any antineoplastic treatment for MIBC. 8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX- 40, CD137). 9. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 10. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. 11. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or the selected chemotherapy regimen, and/or any of their excipients. 12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 13. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 14. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 15. Has an active infection requiring systemic therapy. 16. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority. 17. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 18. Has a known history of active tuberculosis (TB; Bacillus tuberculosis). No TB testing is required unless mandated by local health authority. 19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 20. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. 21. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study intervention. 22. Has had an allogenic tissue/solid organ transplant.
    1. Presenza di CIS diffuso (più foci di CIS) nella vescica. 2. Presenza di UC in qualsiasi sede esterna alla vescica urinaria nei 2 anni precedenti, ad eccezione del CIS di stadio Ta/T1 del tratto superiore se il paziente è stato sottoposto a nefroureterectomia totale.
    3. Presenza di qualsiasi piccola cellula o componente neuroendocrino nel campione di tessuto tumorale. 4. Ulteriore tumore maligno noto in progressione o che ha richiesto una terapia attiva negli ultimi 3 anni.
    5. Presenza di idronefrosi bilaterale durante il periodo di screening. 6. Funzionalità vescicale limitata con frequenza di piccole quantità di urina (<30 mL), incontinenza urinaria, o necessità di autocateterismo o di un catetere a permanenza.
    7. Pregressa radioterapia pelvica/locale o qualsiasi terapia antineoplastica per il MIBC. 8. Terapia pregressa con un agente anti-PD-1, anti-PD-L1 o anti-PDL2 o con un agente diretto contro un altro recettore dei linfociti T co-inibitorio o stimolatorio (ad es. CTLA-4, OX-40, CD137). 9. Vaccinazione con vaccino vivo nei 30 gg precedenti la prima dose del trattamento in studio. Alcuni es. di vaccini vivi comprendono, in via esemplificativa, i vaccini per morbillo, parotite, rosolia, varicella, febbre gialla, rabbia, tubercolosi (BCG) e tifo. I vaccini antinfluenzali stagionali per via iniettiva sono solitamente vaccini inattivati e sono consentiti; i vaccini antinfluenzali intranasali (ad es. FluMist®) sono invece vaccini vivi attenuati e non sono consentiti.
    10. Partecipazione attuale o pregressa a uno studio su un farmaco sperimentale o utilizzo di un dispositivo sperimentale nelle 4 settimane precedenti la prima dose del trattamento in studio. 11. Grave ipersensibilità (= grado 3) a pembrolizumab e/o al regime chemioterapico selezionato, e/o a uno qualsiasi dei loro eccipienti. 12. Diagnosi di immunodeficienza o trattamento cronico con steroidi sistemici (in dosi superiori a 10 mg/die di un equivalente del prednisone) o qualsiasi altra forma di terapia immunosoppressiva nei 7 giorni precedenti la prima dose del farmaco sperimentale. 13. Malattia autoimmune attiva che ha richiesto il trattamento sistemico negli ultimi 2 anni (uso di agenti modificanti la malattia, corticosteroidi o farmaci immunosoppressori). La terapia di sostituzione (ad es. terapia di sostituzione con tiroxina, insulina o corticosteroidi fisiologici in caso di insufficienza ipofisaria o surrenalica) non è considerata una forma di trattam. sistemico.
    14. Anamnesi di polmonite (non infettiva) che ha richiesto il trattamento con steroidi, o polmonite in corso. 15. Infezione attiva che richiede una terapia sistemica. 16. Anamnesi nota positiva per infezione da HIV. Nn è necessario alcun test per il virus dell’immunodeficienza umana (HIV), salvo nei casi in cui ciò sia richiesto dalle autorità sanitarie locali. 17. Anamnesi nota di epatite B (HBsAg reattivo) o epatite C nota in atto (determinazione [qualitativa] dell’RNA del virus dell’epatite C [HCV RNA]). 18. Anamnesi nota di tubercolosi attiva (TB; Bacillus tuberculosis). Non è necessario alcun test per la TB, salvo nei casi in cui ciò sia richiesto dalle autorità sanitarie locali.
    19. Anamnesi o evidenze attuali di qualsiasi condizione, terapia o anomalia di laboratorio che possa confondere i risultati dello studio, interferire con la partecipazione del soggetto allo studio per la sua intera durata o casi in cui non è nel migliore interesse del soggetto partecipare, secondo il giudizio dello sperimentatore curante. 20. Disturbi noti di natura psichiatrica o correlati all’abuso di sostanze che potrebbero interferire con il rispetto dei requisiti dello studio.
    21. Donne in gravidanza o in allattamento, o partecipanti (uomini o donne) che stanno pianificando di avere dei figli nel corso della durata prevista dello studio, a partire dalla visita di screening e per i 180 giorni successivi all’assunzione dell’ultima dose di trattamento sperimentale. 22. Pregresso trapianto allogenico/di organo solido.
    E.5 End points
    E.5.1Primary end point(s)
    Bladder Intact Event-Free Survival
    Sopravvivenza libera da eventi con vescica intatta
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to approximately 71 months.
    Fino a circa 71 mesi.
    E.5.2Secondary end point(s)
    1. Overall Survival (OS)
    2. Metastasis-Free Survival (MFS)
    3. Time to Cystectomy
    4. Time to Occurrence of Non–Muscle-Invasive Bladder Cancer (NMIBC)
    5. Number of Participants Who Experienced One or More Adverse Events (AEs)
    6. Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE)
    7. Change from Baseline in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
    8. Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
    9. Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)
    10.Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L)
    11.Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the Europea Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
    12.Time to Deterioration (TTD) in Physical Functioning (Items 1-5) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
    13 Time to Deterioration (TTD) in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)
    14. Time to Deterioration (TTD) in the Visual Analog Score (VAS) of the European Quality of Life [EuroQoL]-5 Dimensions, 5-level Questionnaire (EQ-5D-5L).
    1. Sopravvivenza globale (OS)
    2. Sopravvivenza libera da metastasi (MFS)
    3. Tempo alla cistectomia
    4. Tempo di insorgenza del carcinoma della vescica non muscolo-invasivo (NMIBC)
    5. Numero di partecipanti che hanno sperimentato uno o più eventi avversi (EA)
    6. Numero di partecipanti che hanno interrotto il trattamento sperimentale per l’insorgenza di un evento avverso (EA)
    7. Variazione rispetto al basale del punteggio combinato relativo a stato di salute globale/qualità di vita (Item 29 e 30) tramite il questionario European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30)
    8. Variazione rispetto al basale del punteggio combinato relativo allo stato funzionale fisico (item 1-5), tramite il questionario European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
    9. Variazione rispetto al basale dei domini relativi alla funzionalità urinaria, della vescica e sessuale del BCI (Bladder Cancer Index)
    10.Variazione rispetto al basale nel questionario EQ-5D-5L (European Quality of Life [EuroQoL]-5 Dimensions, 5-level) su scala visuo- analogica (VAS)
    11.Tempo al deterioramento (TTD) del punteggio combinato relativo a stato di salute globale/qualità di vita (Item 29 e 30) tramite il questionario European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30)
    12.Tempo al deterioramento (TTD) del punteggio combinato relativo allo stato funzionale fisico (item 1-5), tramite il questionario European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLC-C30)
    13.Tempo al deterioramento (TTD) dei domini relativi alla funzionalità urinaria, della vescica e sessuale del BCI (Bladder Cancer Index)
    14.Tempo al deterioramento (TTD) nel questionario EQ-5D-5L (European Quality of Life [EuroQoL]-5 Dimensions, 5-level) su scala visuo- analogica (VAS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 83 months.
    2. Up to approximately 83 months.
    3. Up to approximately 83 months.
    4. Up to approximately 83 months.
    5. Up to approximately 83 months.
    6. Up to approximately 1 year.
    7. Baseline and up to approximately 83 months.
    8. Baseline and up to approximately 83 months.
    9. Baseline and up to approximately 83 months.
    10. Baseline and up to approximately 83 months.
    11. Up to approximately 83 months.
    12. Up to approximately 83 months.
    13. Up to approximately 83 months.
    14. Up to approximately 83 months.
    1. Fino a circa 83 mesi.
    2. Fino a circa 83 mesi.
    3. Fino a circa 83 mesi.
    4. Fino a circa 83 mesi.
    5. Fino a circa 83 mesi.
    6. Fino a circa 1 anno.
    7. Al basale e fino a circa 83 mesi.
    8. Al basale e fino a circa 83 mesi.
    9. Al basale e fino a circa 83 mesi.
    10. Al basale e fino a circa 83 mesi.
    11. Fino a circa 83 mesi.
    12. Fino a circa 83 mesi.
    13. Fino a circa 83 mesi.
    14. Fino a circa 83 mesi.
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA68
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Czechia
    Denmark
    Estonia
    France
    Guatemala
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Latvia
    Malaysia
    Netherlands
    Poland
    Portugal
    Puerto Rico
    Romania
    Spain
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months11
    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: 159
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 477
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 238
    F.4.2.2In the whole clinical trial 636
    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)
    none
    nessun programma
    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 Decision2020-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-11
    P. End of Trial
    P.End of Trial StatusOngoing
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