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    Summary
    EudraCT Number:2018-003809-26
    Sponsor's Protocol Code Number:MK-3475-905
    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 number2018-003809-26
    A.3Full title of the trial
    A Phase 3 Randomized Study of Cystectomy plus Perioperative Pembrolizumab versus Cystectomy Alone in Cisplatin-ineligible Participants with Muscleinvasive Bladder Cancer (KEYNOTE-905)
    Studio Randomizzato di fase III su Pembrolizumab Perioperatorio più Cistectomia versus Cistectomia in pazienti che non sono elegibili al Cisplatino affetti da carcinoma della vescica muscolo-invasivo (KEYNOTE-905)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 trial of perioperative pembrolizumab for cisplatin-ineligible patients with MIBC
    Studio di fase III su Pembrolizumab Perioperatorio in pazienti che non sono elegibili al Cisplatino affetti da MIBC
    A.3.2Name or abbreviated title of the trial where available
    A Phase 3 trial of perioperative pembrolizumab for cisplatin-ineligible patients with MIBC
    Studio di fase III su Pembrolizumab Perioperatorio in pazienti che non sono elegibili al Cisplatino
    A.4.1Sponsor's protocol code numberMK-3475-905
    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., una sussidiaria di Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMSD Italia Srl
    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.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
    Muscle-invasive Bladder Cancer (MIBC)
    Tumore alla vescica muscolo-invasivo (MIBC)
    E.1.1.1Medical condition in easily understood language
    Participants with muscle-invasive urothelial carcinoma who are ineligible for cisplatin-based chemotherapy
    Partecipanti con carcinoma uroteliale muscolo-invasivo che non sono elegibili per la chemioterapia a base di cisplatino
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    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 100000004864
    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 pathologic complete response (pCR) rates obtained in Arm A (preoperative pembrolizumab [MK-3475] and radical cystectomy [RC] + pelvic lymph node dissection [PLND]) and Arm B (RC+PLND), based on central pathologic review, evaluated in participants whose tumors express programmed cell death ligand 1 (PD-L1) combined positive score (CPS) >=10 and all participants, irrespective of CPS score.
    2. To compare event-free survival (EFS) between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), evaluated in participants whose tumors express PD-L1 CPS =10 and all participants, irrespective of CPS score.
    1. Confrontare i tassi di risposta patologica completa (pathologic complete response, pCR) ottenuti nel braccio A (uso preoperatorio di pembrolizumab e cistectomia radicale + dissezione dei linfonodi pelvici [Pelvic Lymph Node Dissection], RC+PLND) e nel braccio B (CR+PLND), in base alla revisione della patologia centrale, valutata nei soggetti con tumori che esprimono PD-L1 CPS >=10 e in tutti i soggetti, indipendentemente dal punteggio CPS.
    2. Confrontare la sopravvivenza libera da eventi (event-free survival, EFS) tra il braccio A (uso perioperatorio di pembrolizumab e CR+PLND) e il braccio B (CR+PLND), valutata nei soggetti con tumori che esprimono PD-L1 CPS =10 e in tutti i soggetti, indipendentemente dal punteggio CPS.
    E.2.2Secondary objectives of the trial
    1. To compare overall survival (OS) between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), evaluated in individuals whose tumors express PD-L1 CPS >=10 and all participants, irrespective of CPS score.
    2. To assess disease-free survival (DFS) in participants from Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND) who are disease free after surgery based on participants whose tumors express PD-L1 CPS >=10 and all participants, irrespective of CPS score.
    3. To compare the rates of pathologic downstaging (pDS) between Arm A (preoperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), evaluated in participants whose tumors express PD-L1 CPS >=10 and all participants, irrespective of CPS score.
    4. To evaluate the safety and tolerability of perioperative pembrolizumab with RC+PLND.
    1. Confrontare la sopravvivenza globale (overall survival, OS) tra il braccio A (uso perioperatorio di pembrolizumab e CR+PLND) e il braccio B (CR+PLND), valutata nei sogg. con tumori che esprimono PD-L1 CPS >=10 e in tutti i soggetti, indipendentemente dal punteggio CPS.
    2. Valutare la sopravv. libera da malattia (disease-free survival, DFS) nei sogg. del braccio A (uso periop. di pembrolizumab e CR+PLND) e del braccio B (CR+PLND), che siano liberi da malattia dopo l’intervento chirurgico, sulla base dei sogg. con tumori che esprimono PD-L1 CPS >=10 e tutti i soggetti, indip. dal punteggio CPS.
    3. Confrontare il tasso di regressione dello stadio patologico (pathologic downstaging, pDS) tra il braccio A (uso preoperatorio di pembrolizumab e CR+PLND) e il braccio B (CR+PLND), valutato nei sogg. con tumori che esprimono PD-L1 CPS >=10 e in tutti i sogg., indipendentemente dal punteggio CPS.
    4. Valutare la sicurezza e la tollerabilità dell’uso perioperatorio di pembrolizumab con CR+PLND.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Merck will conduct Future Biomedical Research on DNA (Blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Merck condurrà una Ricerca Biomedica Futura su campioni di DNA (sangue) raccolti nel corso di questo studio clinico. Tale ricerca ha lo scopo di esaminare vari biomarcatori per rispondere a domande che stanno emergendo e che non sono descritte in altre parti del protocollo (nell’ambito dello studio principale), e verrà condotta solo su campioni di soggetti che abbiano rilasciato apposito consenso.
    L'obiettivo della raccolta dei campioni per la Ricerca Biomedica Futura è quello di esplorare e identificare biomarcatori che contribuiscano scientificamente alla comprensione delle malattie e/o della relative terapie. L'obiettivo ultimo è quello di utilizzare tali informazioni per sviluppare farmaci più sicuri e più efficaci, e/o per garantire che i soggetti ricevano la dose giusta del giusto farmaco al
    momento giusto.
    E.3Principal inclusion criteria
    1. Have a histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (=50%) urothelial histology (histology and presence of muscle invasion to be confirmed by BICR)
    *Participants with mixed histology are eligible provided the urothelial component is >=50%
    *Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible
    *Participants whose tumors contain any neuroendocrine component are not eligible
    2. Have clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT chest and CT or MRI of the abdomen/pelvis), confirmed by BICR
    3. Be deemed eligible for RC + PLND by his/her urologist and/or oncologist and agree to undergo curative intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines
    4. Be ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:
    *Impaired renal function with measured or calculated CrCl 30 to 59 mL/min (calculated by Cockcroft-Gault method or measured by 24-hour urine collection)
    *ECOG Performance Status 2
    *CTCAE v.4 Grade >=2 audiometric hearing loss (25 dB in two consecutive wave ranges))
    *CTCAE v.4 Grade >=2 peripheral neuropathy
    *NYHA Class III heart failure
    5. Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days prior to study enrollment [ICF signed]) which is submitted and adequate for evaluation of histology, muscle invasion and PD-L1 status. In the event the sample is not evaluable for PD-L1, the participant will be assigned to the CPS <10 group for stratification. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides
    6. Must have an ECOG performance status of 0, 1, or 2
    7. Demonstrate adequate organ function (all screening labs should be performed within 14 days prior to randomization)
    8. Participant is male or female at least 18 years of age, at the time of signing the informed consent
    9. A male participant must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
    10. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
    *Not a woman of childbearing potential (WOCBP) or
    *A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after study interventions
    11. 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. Presentare diagnosi istologicamente confermata di tumore della vescica muscolo-invasivo (T2-T4aN0M0) con istologia uroteliale predominante (>=50%) (istologia e presenza di invasione muscolare da confermare mediante BICR).
    - I soggetti con istologia mista sono idonei a condizione che la componente uroteliale sia >=50% come indicato sopra.
    - I carcinomi uroteliali che non hanno origine dalla vescica (ad es. tratto superiore [ureteri, pelvi renale], uretra) non sono idonei.
    - I soggetti con tumori contenenti qualsiasi componente neuroendocrina non sono idonei.
    2. Presentare un tumore della vescica clinicamente non metastatico (N0M0) determinato mediante diagnostica per immagini (TC del torace e TC o RMI di addome/pelvi) e confermato mediante BICR.
    3. Essere considerato idoneo a CR + PLND dall’urologo e/o dall’oncologo e accettare di sottoporsi a CR + PLND standard con intento curativo (inclusa la prostatectomia, se applicabile) secondo le linee guida AUA/ASTRO/ASCO/SUO indicate nell’Appendice 9 (Sezione 10.9 del protocollo).
    4. Essere non idonei al trattamento con cisplatino; tale condizione è definita in base al soddisfacimento di uno dei seguenti criteri:
    - Compromissione della funzionalità renale con clearance della creatinina (CrCl) calcolata o misurata da 30 a 59 ml/min (calcolata mediante metodo di Cockcroft-Gault o raccolta delle urine nell’arco di 24 ore).
    - Stato di validità 2 della scala Gruppo Cooperativo Orientale di Oncologia (Eastern Cooperative Oncology Group, ECOG)
    - Perdita dell’udito audiometrico di grado >=2 (25 decibel in due range di onde consecutive) secondo i criteri comuni di terminologia per gli eventi avversi (Common Terminology Criteria for Adverse Events, CTCAE) v.4.
    - Neuropatia periferica di grado >=2 secondo i criteri CTCAE v.4.
    - Insufficienza cardiaca congestizia di classe III in base all'Associazione di cardiologia di New York (New York Heart Association, NYHA)
    5. Essere stato sottoposto a resezione transuretrale (transurethral resection, TUR) di un tumore della vescica (nei 60 giorni precedenti l’arruolamento nello studio [ICF firmato]) che sia stata presentata e risulti adatta a determinare l’istologia, l’invasione muscolare e lo stato di PD-L1. Nel caso in cui il campione sia non valutabile per PD-L1, il soggetto verrà assegnato al gruppo CPS <10 gruppo per la stratificazione.
    I blocchetti di tessuto fissati in formalina e inclusi in paraffina (Formalin-Fixed, Paraffin Embedded, FFPE) sono preferibili rispetto ai vetrini.
    Nota: In caso di presentazione di vetrini non colorati, i vetrini bioptici nuovi devono essere presentati al laboratorio per gli esami entro 14 giorni dalla data dell’incisione (i dettagli relativi alla presentazione del tessuto tumorale possono essere trovati nel manuale delle procedure).
    6. Avere uno stato di validità pari a 0, 1 o 2 secondo la scala ECOG.
    7. Dimostrare una funzionalità d’organo adeguata secondo la definizione riportata nella Tabella 5 del protocollo (tutti gli esami di laboratorio di screening devono essere eseguiti nei 14 giorni precedenti la randomizzazione).
    Dati demografici
    8. Il soggetto è un soggetto di sesso maschile o femminile di almeno 18 anni di età al momento della firma del consenso informato.

    Per i restanti criteri di inclusione fare riferimento alla sinossi.
    E.4Principal exclusion criteria
    Has a known additional non-urothelial malignancy that is progressing or has required active treatment <=3 years of study randomization
    -Has received any prior systemic anti-neoplastic treatment for MIBC
    -Has an abdomino-pelvic lymph node >=15 mm in the short axis
    -Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
    -Has received prior systemic anti-cancer therapy including investigational agents within 3 years prior to randomization
    -Has received any prior radiotherapy to the bladder
    -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, Bacillus Calmette-Guérin (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
    -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
    -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 the first dose of study drug
    -Has hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
    -Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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
    -Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
    -Has an active infection requiring systemic therapy. Participant may be rescreened once after resolution of the infection
    -Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
    -Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as detectable HCV RNA via qualitative nucleic acid testing) infection
    -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
    -Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
    -Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention
    -Has had an allogenic tissue/solid organ transplant

    Refer to protocol for the rest of exclusion criteria.
    Condizioni mediche
    1. Presenta una nota malignità aggiuntiva non uroteliale che sia in fase di progressione o abbia richiesto un trattamento attivo <=3 anni dalla randomizzazione dello studio.
    Nota: i soggetti con carcinoma cutaneo basocellulare, carcinoma cutaneo squamocellulare o carcinoma in situ (ad es. carcinoma mammario, tumore della cervice) sottoposti a terapia potenzialmente curativa non sono esclusi. I soggetti con precedente tumore della vescica non muscolo-invasivo (non-muscle invasive bladder cancer, NMIBC) che ricevono una terapia prima della randomizzazione non sono esclusi. I soggetti con tumore alla prostata a basso rischio (T1-T2a, punteggio di Gleason =6 e di antigene prostatico specifico [prostate-specific antigen, PSA] <10 ng/ml) trattati con intento definitivo in qualsiasi momento prima dello screening o non trattati in fase di sorveglianza attiva non sono esclusi.
    2. Ha ricevuto qualsiasi precedente trattamento antineoplastico sistemico per MIBC. Nota: è consentito un precedente trattamento per tumore della vescica non muscolo-invasivo (NMIBC) con terapia a base di instillazione intra-vescicale, come BCG o chemioterapia intra-vescicale.
    3. Presenta un linfonodo pelvico-addominale con asse corto >=15 mm.
    4. Precedente terapia con un agente anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un agente diretto contro un altro recettore stimolatorio o co-inibitorio delle cellule T (per es. CTLA-4, OX-40, CD137).
    Terapia precedente/concomitante
    5. Ha ricevuto una precedente terapia antitumorale sistemica, inclusi agenti sperimentali, nei 3 anni precedenti la randomizzazione.
    Nota: i soggetti devono essersi ristabiliti da tutti gli EA dovuti a precedenti terapie (ricevute >3 anni prima della randomizzazione) ed essersi riportati al grado <=1 o al basale. I soggetti con neuropatia di grado <=2 possono essere idonei.
    6. È stato precedentemente sottoposto a radioterapia alla vescica.
    7. Ha ricevuto una vaccinazione con vaccino vivo nei 30 giorni precedenti la prima dose di farmaco dello studio. Esempi di vaccini vivi comprendono, a titolo esemplificativo ma non esaustivo: morbillo, parotite, rosolia, varicella/zoster, febbre gialla, rabbia, bacillo di Calmette-Guérin (BCG) e vaccino tifoideo. I vaccini antinfluenzali stagionali iniettabili sono generalmente vaccini a base di virus inattivati e sono ammessi; tuttavia i vaccini antinfluenzali intranasali (per es. Flu-Mist®) sono vaccini vivi attenuati e non sono consentiti.
    Esperienza precedente/concomitante di partecipazione a uno studio clinico
    8. Partecipazione in corso o pregressa a uno studio su un agente sperimentale oppure utilizzo di un dispositivo sperimentale nelle 4 settimane precedenti alla prima dose di trattamento dello studio.
    Nota: i soggetti che sono entrati nella fase di follow-up di uno studio sperimentale possono partecipare a condizione che siano trascorse 4 settimane dall’ultima dose dell’agente sperimentale precedente.
    9. Diagnosi di immunodeficienza o trattamento in corso con terapia steroidea sistemica cronica (a dosi superiori a 10 mg al giorno di un equivalente del prednisone) o qualsiasi altra forma di terapia immunosoppressiva nei 7 giorni precedenti la prima dose di farmaco dello studio.
    10. Presenta ipersensibilità agli anticorpi monoclonali (incluso pembrolizumab) e/o a uno qualsiasi degli eccipienti.
    11. Presenta una malattia autoimmune in fase attiva che ha richiesto un trattamento sistemico negli ultimi 2 anni (ossia impiego di agenti modificanti la malattia, corticosteroidi o farmaci immunosoppressori). La terapia sostitutiva (es. tiroxina, insulina o terapia sostitutiva con dosi fisiologiche di corticosteroidi per insufficienza surrenalica o pituitaria) non è considerata una forma di trattamento sistemico ed è consentita.

    Per i restanti criteri di esclusione fare riferimento alla sinossi.
    E.5 End points
    E.5.1Primary end point(s)
    1. Pathological Complete Response (pCR) Rate in All Participants
    2. pCR Rate in Participants Whose Tumors Express Programmed Cell Death Ligand 1 (PD-L1) at a Combined Positive Score (CPS) >=10
    3. Event-Free Survival (EFS) in All Participants
    4. EFS in Participants Whose Tumors Express PD-L1 at a CPS >=10
    1. Tasso di risposta patologica completa (pCR) in tutti i partecipanti
    2. Tasso di pCR nei partecipanti i cui tumori esprimono PD-L1 a un CPS >=10
    3. Sopravvivenza libera da eventi (EFS) in tutti i partecipanti
    4. EFS nei partecipanti i cui tumori esprimono PD-L1 a un CPS >=10
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 3 months (Time of surgery)
    2. Up to approximately 3 months (Time of surgery)
    3. Up to approximately 5.5 years
    4. Up to approximately 5.5 years
    1. Fino a circa 3 mesi (Tempo di intervento)
    2. Fino a circa 3 mesi (Tempo di intervento)
    3. Fino a circa 5.5 anni
    4. Fino a circa 5.5 anni
    E.5.2Secondary end point(s)
    1. Overall Survival (OS) in All Participants
    2. OS in Participants Whose Tumors Express PD-L1 at a CPS >=10
    3. Disease-Free Survival (DFS) in All Participants
    4. DFS in Participants Whose Tumors Express PD-L1 at a CPS >=10
    5. Pathologic Downstaging (pDS) Rate in All Participants
    6. pDS Rate in Participants Whose Tumors Express PD-L1 at a CPS >=10
    7. Percentage of Participants Experiencing an Adverse Event (AE)
    8. Percentage of Participants Discontinuing Study Treatment due to an AE
    9. Percentage of Participants Experiencing Perioperative Complications
    1. Sopravvivenza globale (OS) in tutti i partecipanti
    2. OS nei partecipanti i cui tumori esprimono PD-L1 a un CPS >=10
    3. Sopravvivenza libera da malattia (DFS) in tutti i partecipanti
    4. DFS nei partecipanti i cui tumori esprimono PD-L1 a un CPS >=10
    5. Tasso patologico di rallentamento (pDS) in tutti i partecipanti
    6. Tasso pDS nei partecipanti i cui tumori esprimono PD-L1 a un CPS >=10
    7. Percentuale di partecipanti che hanno manifestato un Evento Avverso (AE)
    8. Percentuale di partecipanti che interrompono il trattamento in studio a causa di un Evento Avverso (AE)
    9. Percentuale di partecipanti che hanno manifestato una complicazione perioperatoria
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 6.5 years
    2. Up to approximately 6.5 years
    3. Up to approximately 5.5 years
    4. Up to approximately 5.5 years
    5. Up to approximately 3 months (Time of surgery)
    6. Up to approximately 3 months (Time of surgery)
    7. Up to approximately 6.5 years
    8. Up to approximately 1 year
    9. Up to approximately 1 year
    1. Fino a circa 6.5 anni
    2. Fino a circa 6.5 anni
    3. Fino a circa 5.5 anni
    4. Fino a circa 5.5 anni
    5. Fino a circa 3 mesi (Tempo di intervento)
    6. Fino a circa 3 mesi (Tempo di intervento)
    7. Fino a circa 6.5 anni
    8. Fino a circa 1 anno
    9. Fino a circa 1 anno
    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 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) 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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Cistectomia
    Cystectomy
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA105
    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
    Belgium
    Canada
    Denmark
    France
    Germany
    Hungary
    Ireland
    Israel
    Italy
    Korea, Republic of
    Mexico
    Poland
    Russian Federation
    Spain
    Sweden
    Thailand
    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 months10
    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 months10
    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: 305
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 305
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 408
    F.4.2.2In the whole clinical trial 610
    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)
    The subjects will be treated per standard of care post participation in the study.
    I soggetti saranno trattati con standard di cura dopo la partecipazione allo studio.
    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 Decision2019-06-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-07
    P. End of Trial
    P.End of Trial StatusOngoing
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