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    Summary
    EudraCT Number:2019-003633-41
    Sponsor's Protocol Code Number:MK-3475-991
    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 number2019-003633-41
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Plus ADT Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (KEYNOTE-991)
    Studio di fase III, randomizzato, in doppio cieco su pembrolizumab (MK-3475) più enzalutamide più ADT rispetto a placebo più enzalutamide più ADT in soggetti con cancro della prostata ormone-sensibile metastatico (mHSPC) (KEYNOTE-991)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 Study of Pembrolizumab/Placebo plus Enzalutamide plus ADT in mHSPC
    Studio di fase 3 su Pembrolizumab/Placebo più Enzalutamide più ADT in soggetti con mHSPC
    A.3.2Name or abbreviated title of the trial where available
    Phase 3 Study of Pembrolizumab/Placebo plus Enzalutamide plus ADT in mHSPC
    Studio di fase 3 su Pembrolizumab/Placebo più Enzalutamide più ADT in soggetti con mHSPC
    A.4.1Sponsor's protocol code numberMK-3475-991
    A.5.4Other Identifiers
    Name:INDNumber:122753
    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.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 number0039090636191371
    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. - n. AIC: EU/1/15/1024/002
    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 Xtandi (enzalutamide) capsule
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma US, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENZALUTAMIDE
    D.3.9.1CAS number 915087-33-1
    D.3.9.2Current sponsor code-
    D.3.9.4EV Substance CodeSUB77412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
    Cancro della prostata ormone-sensibile metastatico (mHSPC)
    E.1.1.1Medical condition in easily understood language
    Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
    Cancro della prostata ormone-sensibile metastatico (mHSPC)
    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 PT
    E.1.2Classification code 10036909
    E.1.2Term Prostate cancer metastatic
    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 PT
    E.1.2Classification code 10071119
    E.1.2Term Hormone-dependent prostate 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 pembrolizumab (MK-3475) plus enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus enzalutamide plus ADT with respect to radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded
    independent central review (BICR) where soft tissue will be assessed per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and bone disease will be assessed per PCWG criteria.
    2. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to overall survival (OS).
    1. Confrontare pembrolizumab (MK-3475) più enzalutamide più terapia di deprivazione androgenica (ADT) rispetto a placebo più enzalutamide più ADT in termini di rPFS secondo i criteri RECIST 1.1 modificati dal PCWG valutati mediante BICR dove i tessuti molli saranno valutati secondo RECIST 1.1 modificato per seguire un massimo di 10 lesioni target e un massimo di 5 lesioni target per organo, e la malattia ossea sarà valutata secondo i criteri PCWG.
    2. Confrontare pembrolizumab più enzalutamide più ADT rispetto a placebo più enzalutamide più ADT in termini di OS.
    E.2.2Secondary objectives of the trial
    1. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to TFST.
    2. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to TTSSRE.
    3. To assess pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to the: time to PSA progression; time to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1, as assessed by BICR; TTPP; PFS2.
    4. To assess pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to the: PSA response rate; PSA undetectable rate; and ORR and DOR per PCWG-modified RECIST 1.1 as assessed by BICR.
    5. To assess the safety and tolerability of pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT.
    1. Confrontare pembrolizumab più enzalutamide più ADT rispetto a placebo più enzalutamide più ADT in termini di TFST.
    2. Confrontare pembrolizumab più enzalutamide più ADT rispetto a placebo più enzalutamide più ADT in termini di TTSSRE.
    3. Valutare pembrolizumab più enzalutamide più ADT rispetto a placebo più enzalutamide più ADT in termini di: Tempo alla progressione del PSA; Tempo alla progressione radiografica dei tessuti molli secondo le regole RECIST 1.1 modificate dal PCWG e valutate mediante BICR; TTPP; PFS2.
    4. Valutare pembrolizumab più enzalutamide più ADT rispetto a placebo più enzalutamide più ADT in termini di: Tasso di risposta del PSA; Tasso di PSA non rilevabile; ORR e DOR secondo i criteri RECIST 1.1 modificati dal PCWG e valutati mediante BICR.
    5. Valutare la sicurezza e la tollerabilità di pembrolizumab più enzalutamide più ADT rispetto a placebo più enzalutamide più ADT.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Has histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report and confirmed by the investigator.
    2. Has metastatic disease as assessed by investigator and verified by BICR (prior to randomization) by either >=2 bone lesions on bone scan and/or visceral disease (eg, lung or liver) by CT/MRI. Participants whose metastatic disease is limited to lymph nodes are not eligible.
    3. Once randomized, participant must be willing to maintain continuous ADT with a LHRH agonists or antagonists during study treatment or have a history of bilateral orchiectomy.
    4. Has an ECOG performance status of 0 or 1 assessed within 10 days of randomization.
    5. Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses for >=4 weeks prior to randomization.
    6. Demonstrates adequate organ function; all screening labs should be performed in central laboratory within 10 days of the first dose of study intervention.
    7. Is male, >=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 120 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. Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
    10. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study.
    11. Has provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed; other exceptions may be considered after Sponsor consultation). Participants with bone only or bone predominant disease
    may provide a bone biopsy sample (decalcification not allowed). However, if obtaining a new biopsy is not feasible, then participants may provide an archival tumor tissue sample after Sponsor consultation (SCF). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archive
    tissue. Adequacy of these specimens for PD-L1 biomarker analysis will be required by a central laboratory prior to randomization.
    1. Presenta diagnosi confermata istologicamente o citologicamente (se previsto dai regolamenti delle autorità sanitarie locali) di adenocarcinoma della prostata non a piccole cellule. La diagnosi deve essere indicata in un referto patologico e confermata dallo sperimentatore.
    2. È affetto da malattia metastatica secondo la valutazione dello sperimentatore e la verifica mediante revisione centrale indipendente in cieco (BICR) (prima della randomizzazione), con >=2 lesioni ossee alla scintigrafia ossea e/o malattia viscerale (ad es. polmonare o epatica) evidenziata da TC/RM. I partecipanti la cui malattia metastatica sia limitata ai linfonodi non sono eleggibili.
    3. Una volta randomizzati, i partecipanti devono acconsentire a mantenere un’ADT continua con agonisti o antagonisti dell’LHRH durante il trattamento sperimentale, oppure presentare un’anamnesi di orchiectomia bilaterale.
    4. Ha un performance status ECOG pari a 0 o 1, valutato entro 10 gg dalla randomizzazione.
    5. I partecipanti che ricevono una terapia di riassorbimento osseo (tra cui, a titolo di esempio, bifosfonato o denosumab) devono essere rimasti a una dose stabile per >=4 settimane prima della randomizzazione.
    6. Presenta una funzionalità d’organo adeguata; tutti gli esami di laboratorio devono essere condotti nel laboratorio centrale nei 10 giorni precedenti la prima dose di trattamento sperimentale.
    7. Soggetto di sesso maschile, >=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 120 giorni dopo l’ultima somministrazione di farmaco sperimentale:
    • Astenersi dal donare sperma PIÙ:
    - Essere astinenti da rapporti eterosessuali come stile di vita preferito e abituale (astinenza a lungo termine e persistente) e accettare di rimanere astinenti 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. Nota: gli uomini con una partner incinta o che allatta al seno devono acconsentire ad astenersi dai rapporti
    sessuali penetrativi vaginali o a utilizzare un profilattico maschile durante ogni rapporto penetrativo vaginale.
    9. I partecipanti di sesso maschile devono acconsentire a utilizzare un preservativo maschile in qualsiasi attività che consenta il passaggio di eiaculato a un’altra persona di qualsiasi sesso.
    10. Il partecipante (o il rappresentante legalmente riconosciuto, ove applicabile) fornisce il consenso/assenso informato scritto per lo studio.
    11. Ha fornito una biopsia di nuova acquisizione con ago tranciante o escissionale (eseguita nei 12 mesi prec lo screening) di tessuto molle che in precedenza non è stato sottoposto a radiazioni (i campioni ottenuti da tumori in progressione in un’area precedentemente sottoposta a radioterapia sono consentiti; altre eccezioni possono essere considerate previa consultazione con lo Sponsor). I partecipanti con malattia esclusivamente o prevalentemente ossea possono fornire un campione bioptico di tessuto osseo (decalcificazione non ammessa). Tuttavia, qualora non sia possibile ottenere una nuova biopsia, i partecipanti possono fornire un campione di tessuto tumorale in archivio previa consultazione con lo Sponsor (SCF). È preferibile un blocco di tessuto tumorale fissato in formalina e incluso in paraffina (FFPE) rispetto al vetrino. È preferibile una biopsia di nuova acquisizione rispetto a un tessuto presente in archivio. L’adeguatezza di questi campioni per l’analisi dei biomarcatori di PD-L1 sarà richiesta da un lab centralizzato prima della randomiz.
    E.4Principal exclusion criteria
    1. Has a known additional malignancy that is progressing or has required active treatment in the last 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are not excluded.
    2. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment.
    3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.
    4. 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.
    5. Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications.
    6. Has a gastrointestinal disorder affecting absorption.
    7. Is unable to swallow tablets/capsules.
    8. Has an active infection (including tuberculosis) requiring systemic therapy.
    9. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    10. Has known active HIV, hepatitis B virus or HCV. Testing for Hepatitis B and Hepatitis C is not required unless mandated by local regulation.
    11. Has known or suspected CNS metastases and/or carcinomatous meningitis.
    12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
    13. Has a history of seizure or any condition that may predispose to seizure (including, but not limited to prior cerebrovascular accident, transient ischemic attack, or brain arteriovenous malformation; or intracranial masses such as a schwannoma or meningioma that is causing edema or mass effect).
    14. Has a history of loss of consciousness within 12 months of the Screening Visit.
    15. Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization.
    16. Has New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure unless a screening echocardiogram or multigated acquisition scan performed within 3 months prior to randomization date demonstrates a left ventricular ejection fraction >45%.
    17. Has a history of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsades de pointes). 18. Has a history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
    19. Has hypotension as indicated by systolic blood pressure <86 millimeters of mercury (mmHg) at the Screening Visit.
    20. Has bradycardia as indicated by a heart rate of <50 beats per minute on the Screening ECG.
    21. Has uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at the Screening visit.
    22. Has severe hypersensitivity (Grade =3) to pembrolizumab and/or any of its excipients.
    23. Has hypersensitivity reaction to enzalutamide or any of its capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.
    Fo remaining criteria refer to protocol.
    1. Ha un ulteriore tumore maligno noto in progres o che ha richiesto un trattam attivo negli ultimi 3 anni. I partecip con carcinoma basocellulare della cute, carcinoma squamocellulare della cute o carcinoma in situ trattato con una terap potenzialmente curativa non sono esclusi.
    2. Malattia autoimm attiva che ha richiesto il trattam sistemico negli ultimi 2 anni (uso di ag modificanti la malattia, corticost o farmaci immunosop). La terap di sostituz (ad es. tiroxina, insulina o terap di sostituz fisiologica con corticost per insuff ipofisaria o surrenalica ecc.) non è considerata una forma di trattam sistemico.
    3. Diagnosi di immunodef o trattam cronico con steroidi sistemici (in dosi superiori a 10 mg/die di un equivalente del prednisone) o qualsiasi altra forma di terap immunosop nei 7 gg prec la prima dose del trattam sperimentale.
    4. Anamnesi oppure attuale presenza di evidenze di qualsiasi condizione, terap o anomalia di lab che possa confondere i risultati dello stu, interferire con la partecipaz del sog allo stu per la sua intera durata o casi in cui non è nel migliore interesse del sog partecipare, secondo il giudizio dello speriment curante.
    5. Intervento chirurgico importante, tra cui intervento locale alla prostata (esclusa la biopsia della prostata), nei 28 gg prec la randomiz e recupero non adeguato dalle tossicità e/o complicanze.
    6. Patologia gastrointestinale che influisce sull’assorbimento (ad es. gastrectomia, ulcera peptica attiva negli ultimi 3 mesi).
    7. Non è in grado di deglutire compresse o capsule.
    8. Ha un’infezione attiva (tra cui tubercolosi) che richiede una terap sistemica.
    9. Anamnesi positiva per polmonite (non infettiva) che ha richiesto il trattam con steroidi o attuale presenza di polmonite.
    10. Infezione nota da HIV, virus dell’epatite B (ad es. Ag di superficie del virus dell’epatite B reattivo) o HCV (ad es. determinazione [qualitativa] di HCV-RNA) in atto. Non è necessario alcun test per l’epatite B e C, salvo nei casi in cui sia richiesto dai regolamenti locali.
    11. Metastasi a livello del SNC note o sospette e/o meningite carcinomatosa.
    12. Disturbi psichiatrici o da abuso di sostanze noti che potrebbero interferire con l’aderenza ai requisiti dello stu.
    13. Anamnesi di convulsioni o qualsiasi condiz che possa predisporre alle convulsioni (tra cui, a titolo di es, prec accidente cerebrovascolare o attacco ischemico transitorio, o malformazione artero-venosa del cervello; oppure masse intracraniche come uno schwannoma o meningioma che causa edema o effetto massa).
    14. Anamnesi di perdita di coscienza nei 12 mesi prec la visita di screening.
    15. Infarto miocardico o angina non controllata nei 6 mesi prec la randomiz.
    16. È affetto da o presenta anamnesi di insuf cardiaca congestizia di classe III o IV secondo la classificazione della New York Heart Association, a meno che un ecocardiogramma o un’angiocardioscintigrafia di screening eseguiti nei 3 mesi prec la data di randomiz dimostrino una frazione di eiezione ventricolare sinistra >45%.
    17. Anamnesi di aritmie ventricolari clinicamente significative (ad es. tachicardia ventricolare, fibrillazione ventricolare, torsione di punta).
    18. Anamnesi di blocco atrioventricolare di secondo o terzo grado Mobitz II senza pacemaker permanente in sede.
    19. Ipotensione indicata da pressione arteriosa sistolica <86 millimetri di mercurio (mmHg) alla visita di screening.
    20. Bradicardia indicata da una frequenza cardiaca di <50 battiti al minuto nell’ECG dello screening.
    21. Ipertensione non controllata indicata da pressione arteriosa sistolica >170 mmHg o pressione arteriosa diastolica >105 mmHg alla visita di screening.
    22. Grave ipersensibilità (= grado 3) a pembrolizumab e/o a uno qualsiasi dei suoi eccipienti.
    Per i restanti criteri fare riferimento al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    1. Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review
    2. Overall Survival (OS)
    1. Sopravvivenza libra da progressione radiografica (rPFS) modificata dal PCWG in base ai criteri RECIST 1.1 e verificati mediante revisione centrale indipendente in cieco,
    2. Sopravvivenza globale (OS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 77 months
    2. Up to approximately 77 months
    1. Fino a circa 77 mesi
    2. Fino a circa 77 mesi
    E.5.2Secondary end point(s)
    1. Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)
    2. Time to Symptomatic Skeletal-Related Event (TTSSRE)
    3. Time to Prostate-specific Antigen (PSA) Progression
    4. Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review
    5. Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24 Hours") and Opiate Use
    6. Time from Randomization to Disease Progression as Determined by Investigator Assessment after Next-line of Therapy or Death from Any Cause, Whichever Occurs First (PFS2)
    7. Prostate-specific Antigen (PSA) Response Rate
    8. Prostate-specific antigen (PSA) Undetectable Rate
    9. Objective Response Rate (ORR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review
    10. Duration of Response (DOR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review
    11. Number of Participants Who Experience an Adverse Event (AE)
    12. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
    1. Tempo dalla randomizzazione all’inizio della prima terapia antitumorale successiva o al decesso (TFST)
    2. Tempo dalla randomizzazione al primo evento sintomatico legato allo scheletro (TTSSRE)
    3. Tempo alla Progressione dell'antigene prostatico specifico (PSA)
    4. Tempo alla progressione radiografica dei tessuti molli modificata dal PCWG in base ai criteri RECIST 1.1 e verificati mediante revisione centrale indipendente in cieco.
    5. Tempo dalla randomizzazione alla progressione del dolore (TTPP) basato sulla voce 3 della scala BPI-SF “peggior dolore in 24 ore” e sull’uso di oppiacei
    6. Tempo dalla randomizzazione alla progressione di malattia (PFS2) determinato dalla valutazione dello sperimentatore della progressione radiologica o clinica dopo la linea di terapia successiva o il decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo.
    7. Tasso di risposta del PSA
    8. Tasso di PSA non rilevabile
    9. Tasso di Risposta Obiettiva (ORR) modificata dal PCWG in base ai criteri RECIST 1.1 e verificati mediante revisione centrale indipendente in cieco.
    10. Durata della risposta (DOR) modificata dal PCWG in base ai criteri RECIST 1.1 e verificati mediante revisione centrale indipendente in cieco.
    11. Numero di partecipanti con esperienza di evento avverso (EA)
    12. Numero di partecipanti che Interrompono il trattamento di studio a causa di un evento avverso (EA)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 77 months
    2. Up to approximately 77 months
    3. Up to approximately 77 months
    4. Up to approximately 77 months
    5. Up to approximately 77 months
    6. Up to approximately 77 months
    7. Up to approximately 77 months
    8. Up to approximately 77 months
    9. Up to approximately 77 months
    10. Up to approximately 77 months
    11. Up to approximately 77 months
    12. Up to approximately 77 months
    1. Fino a circa 77 mesi
    2. Fino a circa 77 mesi
    3. Fino a circa 77 mesi
    4. Fino a circa 77 mesi
    5. Fino a circa 77 mesi
    6. Fino a circa 77 mesi
    7. Fino a circa 77 mesi
    8. Fino a circa 77 mesi
    9. Fino a circa 77 mesi
    10. Fino a circa 77 mesi
    11. Fino a circa 77 mesi
    12. Fino a circa 77 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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, and/or the mechanism of action, between the experimental and comparator arms, using blood and/or tumor tissue. To compare the experimental and comparator arm with respect to the change from baseline disease-related symptoms and health-related quality of life questionnaires.
    Identificare biomarcatori molecolari (genomico, metabolico e/o proteomico) che possono essere indicativi di risposta/resistenza clinica, sicurezza e/o meccanismo d'azione, tra il braccio sperimentale e quello di confronto, mediante l’utilizzo di sangue e/o tessuto tumorale. Confrontare il braccio sperimentale e quello di confronto in termini di cambiamento rispetto ai sintomi basali correlati alla malattia e ai questionari sulla qualità della vita relativi alla salute.
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA110
    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
    Brazil
    Canada
    Chile
    China
    Colombia
    Gambia
    Israel
    Japan
    Korea, Republic of
    Mexico
    New Zealand
    Peru
    Russian Federation
    Taiwan
    Thailand
    Turkey
    United States
    Austria
    Denmark
    Finland
    France
    Ireland
    Italy
    Netherlands
    Poland
    Spain
    Switzerland
    United Kingdom
    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 months5
    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 months5
    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: 406
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 826
    F.2 Gender
    F.2.1Female No
    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 state64
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 626
    F.4.2.2In the whole clinical trial 1232
    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
    Nessuno
    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 Decision2020-02-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-15
    P. End of Trial
    P.End of Trial StatusOngoing
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