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    Summary
    EudraCT Number:2015-002067-41
    Sponsor's Protocol Code Number:MK3475-158
    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:2021-01-20
    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 number2015-002067-41
    A.3Full title of the trial
    A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects with Advanced Solid Tumors (KEYNOTE 158)
    Studio Clinico su pembrolizumab (MK-3475) per valutare biomarcatori predittivi in soggetti affetti da tumori solidi avanzati (KEYNOTE 158)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PhII Trial of Pembrolizumab in Advanced Solid Tumors
    Studio di fase II su Pembrolizumab in tumori solidi avanzati
    A.3.2Name or abbreviated title of the trial where available
    KEYNOTE-158
    KEYNOTE-158
    A.4.1Sponsor's protocol code numberMK3475-158
    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 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 number00360636380371
    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 code.
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    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
    -Anal Squamous Cell Carcin (CA) -Biliary Adenocarcin - Neuroendocrine Tumors (well-moderately-differentiated) - Endometrial CA (sarcomas and mesenchymal tumors excluded) - Cervical Squamous and Vulvar Squamous Cell CA - Small Cell Lung CA Malignant Pleural Mesothelioma - Thyroid CA (Papillary or Follicular Subtype) -Salivary Gland CA OR (sarcomas and mesenchymal tumors are excluded) - Other advanced solid tumor with the exception of colorectal carcinoma which is Microsatellite Instability – High
    -Carcinoma anale cell squamose -Adenocarcin tratto bili-Carcin neuroendocrini (ben e moderatamente differenziati) -Carcin endometriale (sarcomi e tumori mesenchimali esclusi) -Carcin cervicale e vulvare a cell squamose -Carcin polmonare a piccole cell Mesotelioma pleurico maligno -Carcin tiroideo (variante papillare o follicolare) -Carcin ghiand salivari (sarcomi e tumori mesenchimali esclusi) -Altri tumori solidi avanz (eccez. carcin colorettale) che prevedono un'elevata instabilità microsatel.
    E.1.1.1Medical condition in easily understood language
    Advanced Solid Tumors
    Tumori Solidi Avanzati
    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 10065143
    E.1.2Term Malignant solid tumour
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Objective 1: To evaluate the ORR to pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in biomarker-unselected subjects with any one of multiple types of advanced (metastatic and/or unresectable) solid tumors (Groups A-J)
    Objective 2: To evaluate the ORR to pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in biomarker-selected subjects with any one of multiple types of advanced (metastatic and/or unresectable) solid tumors (Groups A-K). The primary biomarkers to be evaluated are (1) tumor expression of PD-L1 by IHC (Groups A-J), (2) tumor GEP by RNA analysis (Groups A-J), and (3) tumor MSI by DNA analysis (Groups A-J) or routine local testing (Group K).
    Obiettivo 1: Valutare l'ORR a pembrolizumab, sulla base dei criteri RECIST 1.1, mediante revisione radiologica indipendente centralizzata, con biomarcatore non selezionato in soggetti affetti da uno qualsiasi dei molteplici tipi di tumore solido in fase avanzata (metastatico e/o non asportabile chirurgicamente) (Gruppi A-J).
    Obiettivo 2: Valutare l'ORR a pembrolizumab, sulla base dei criteri RECIST 1.1, mediante revisione radiologica indipendente centralizzata, con biomarcatore selezionato in soggetti affetti da uno qualsiasi dei molteplici tipi di tumore solido (Gruppi A-K). I biomarcatori principali da valutare saranno (1) l'espressione tumorale di PD-L1 mediante IHC (Gruppi A-J), (2) il GEP del tumore mediante l'analisi dell'RNA (Gruppi A-J) e (3) MSI del tumore mediante l'analisi del DNA (Gruppi A-J) o test di routine locale (Gruppo K).
    E.2.2Secondary objectives of the trial
    In subjects receiving pembrolizumab (Groups A-J) to evaluate:
    -DOR (based on RECIST 1.1 as assessed by independent central radiologic review) and the relationship between DOR and tumor PD-L1 expression and GEP score
    -PFS (based on RECIST 1.1 as assessed by independent central radiologic review) and the relationship between PFS and tumor PD-L1 expression and GEP score
    -OS and the relationship between OS and tumor PD-L1 expression and GEP score
    In subjects receiving pembrolizumab (Groups A-K) to evaluate:
    -the safety and tolerability of pembrolizumab
    -DOR (based on RECIST 1.1 as assessed by independent central radiologic review) in subjects receiving pembrolizumab and the relationship between DOR and tumor MSI-H status
    -PFS (based on RECIST 1.1 as assessed by independent central radiologic review)and the relationship between PFS and tumor MSI-H status
    -OS and the relationship between OS and tumor MSI-H status
    -Pembrolizumab pharmacokinetics (PK) for the 200mg IV Q3W fixed dosing regimen
    Nei soggetti trattati con pembrolizumab (Gruppi A-J), valutare:
    -DOR, secondo i criteri RECIST 1.1 mediante revisione radiologica indipendente centralizzata, il rapporto tra DOR ed espressione tumorale di PD-L1 e punteggio GEP
    -PFS secondo i criteri RECIST 1.1 mediante revisione radiologica indipendente centralizzata, il rapporto tra PFS ed espressione tumorale di PD-L1 e punteggio GEP
    -OS ed il rapporto tra OS ed espressione tumorale di PD-L1 e punteggio GEP
    Nei soggetti trattati con pembrolizumab (Gruppi A-K), valutare:
    -sicurezza e la tollerabilit¿ di pembrolizumab
    -DOR secondo i criteri RECIST 1.1 mediante revisione radiologica indipendente centralizzata, il rapporto tra DOR e stato MSI-H del tumore
    -PFS secondo i criteri RECIST 1.1 mediante revisione radiologica indipendente centralizzata, il rapporto tra PFS e stato MSI-H del tumore
    -OS, nonch¿ il rapporto tra OS e stato MSI-H del tumore
    -farmacocinetica (PK) di pembrolizumab per il regime a dose fissa di 200 mg EV Q3W
    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 (estratti dal 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 ¿ quello di esplorare e identificare biomarcatori che contribuiscano scientificamente alla comprensione delle malattie e/o delle relative terapie. L'obiettivo ultimo ¿ 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. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
    2.Be >=18 years of age on the day of signing informed consent.
    3. Have a histologically or cytologically-documented, advanced (metastatic and/or unresectable) solid tumor that is incurable and for which prior standard first-line treatment has failed. Patients must have
    progressed on or be intolerant to therapies that are known to provide clinical benefit. There is no limit to the number of prior treatment regimens.
    4. Have one of the following advanced (unresectable and/or metastatic) tumor types:
    (A) Anal Squamous Cell Carcinoma,
    (B) Biliary Adenocarcinoma (gallbladder or biliary tree (intrahepatic or extrahepatic cholangiocarcinoma) except Ampulla of Vater Cancers,
    (C) Neuroendocrine Tumors (well- and moderately-differentiated), of the lung, appendix, small intestine, colon, rectum, or pancreas,
    (D) Endometrial Carcinoma (sarcomas and mesenchymal tumors are excluded),
    (E) Cervical Squamous Cell Carcinoma,
    (F) Vulvar Squamous Cell Carcinoma,
    (G) Small Cell Lung Carcinoma,
    (H) Mesothelioma (Malignant Pleural Mesothelioma),
    (I) Thyroid Carcinoma (Papillary or Follicular Subtypes),
    (J) Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded)
    OR
    (K) Any advanced solid tumor (except CRC), which is MSI-H.
    5. Have submitted an evaluable tissue sample for biomarker analysis from a tumor lesion not previously irradiated (exceptions may be considered after consultation with and approval by the Sponsor) (See Procedure Manual for detailed instructions). The tumor tissue submitted for analysis must be from a single tumor tissue specimen and of sufficient quantity and quality to allow assessment of ALL required primary biomarkers.
    6. If enrollment in Groups A-J has moved to biomarker enrichment, have a tumor that is positive for one or more of the pre-specified primary
    biomarker(s), as assessed by the central laboratory. These enrichment biomarkers may be PD-L1 expression by IHC (at a percentage to be prespecified), a positive tumor RNA GEP score (at a prespecified cut-off), and/or tumor MSI-H.
    7. Have radiologically measurable disease based on RECIST 1.1. Independent central radiologic review must confirm the presence of radiologically measureable disease based on RECIST 1.1 for the subject to be eligible to participate in the trial (see Site Imaging Manual for detailed instructions). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
    8. Have a performance status of 0 or 1 on the ECOG Performance Scale. This performance status must be confirmed within 3 days prior to the first dose of pembrolizumab or the subject must be excluded.
    9. Life expectancy of at least 3 months.
    10. Demonstrate adequate organ function as described in the protocol.
    11. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.


    Refer to protocol for the rest of inclucion criteria.
    1. Essere disposto e in grado di fornire un consenso informato scritto alla sperimentazione. Il soggetto può inoltre decidere di fornire il consenso per la Ricerca Biomedica Futura (RBF). Tuttavia, il soggetto può partecipare alla sperimentazione principale senza prendere parte alla Ricerca Biomedica Futura.
    2. Avere >= 18 anni d’età alla data della firma del consenso informato
    3. Presentare un tumore solido istologicamente o citologicamente documentato in fase avanzata (metastatico e/o non asportabile chirurgicamente) che sia incurabile e che non abbia risposto in precedenza ad una prima linea di trattamento. I pazienti devono mostrare progressione della malattia o essere intolleranti alle terapie che sono note per fornire un beneficio clinico. Non vi sono limiti al numero di regimi terapeutici precedenti.
    4. Essere affetti da uno dei seguenti tipi di tumore solido in fase avanzata (non asportabile chirurgicamente e/o metastatico):
    (A) Carcinoma anale squamocellulare
    (B) Adenocarcinoma del tratto biliare (cistifellea e albero biliare), colangiocarcinoma intraepatico o extraepatico, tranne il carcinoma dell’Ampolla di Vater
    (C) Carcinomi neuroendocrini (bene o moderatamente differenziati), del polmone, dell’appendice, dell’intestino tenue, del colon retto, o del pancreas
    (D) Carcinoma endometriale (sarcomi e tumori mesenchimali sono esclusi)
    (E) Carcinoma cervicale squamocellulare
    (F) Carcinoma vulvare squamocellulare
    (G) Carcinoma polmonare a piccole cellule
    (H) Mesotelioma (mesotelioma pleurico maligno)
    (I) Carcinoma tiroideo (variante papillare o follicolare)
    (J) Carcinoma delle ghiandole salivaria (sarcomi e tumori mesenchimali sono esclusi)
    OPPURE
    (K) Qualsiasi tumore solido in fase avanzata (tranne il CRC), che sia MSI-H.
    5. Avere fornito un campione tissutale valutabile per l’analisi dei biomarcatori su una lesione tumorale non precedentemente irradiata (le eccezioni possono essere prese in considerazione previa consultazione dello Sponsor).(Vedere Manuale delle Procedure per maggiori dettagli) . Il tessuto tumorale inviato per l’analisi deve derivare da un unico campione biologico di tessuto tumorale e disponibile in quantità e qualità sufficienti da consentire la valutazione di TUTTI i biomarcatori primari necessari.
    6. Laddove l’arruolamento ai Gruppi A-J sia stato trasferito all’arricchimento dei biomarcatori, i soggetti devono presentare un tumore positivo a uno o più biomarcatori primari prespecificati, come valutato dal laboratorio centralizzato. Tali biomarcatori di arricchimento possono essere l’espressione di PD-L1 mediante IHC (in una percentuale da prespecificare), un punteggio GEP dell’RNA di positività del tumore (ad una soglia limite [cut-off] prespecificata) e/o stato di MSI-H del tumore
    7. Presentare una malattia radiologicamente misurabile secondo i criteri RECIST 1.1. La revisione radiologica indipendente centralizzata deve confermare la presenza di una malattia radiologicamente misurabile sulla base dei criteri RECIST 1.1 affinché il soggetto possa essere ammesso a partecipare alla sperimentazione. Le lesioni tumorali localizzate in una zona già sottoposta a radiazioni sono considerate misurabili se vi si dimostra la progressione.
    8. Avere uno stato di validità (Performance Status) di 0 o 1 secondo la scala dell’Eastern Cooperative Oncology Group (ECOG). Tale stato deve essere confermato nei tre giorni precedenti l’assunzione della prima dose di pembrolizumab, altrimenti il soggetto sarà escluso.
    9. Aspettativa di vita di almeno 3 mesi.
    10. Dimostrare una funzionalità organica adeguata come descritto nel protocollo

    Per i restanti criteri di inclusione fare riferimento al Protocollo.
    E.4Principal exclusion criteria
    1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.
    2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
    3. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) or treatment with drugs (e.g. neomercazol, carbamazole, etc.) that function to decrease the generation of thyroid hormone by a hyperfunctioning thyroid gland (e.g in Graves' disease) is not considered a form of systemic treatment of an autoimmune disease.
    4. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., <= Grade 1 or at baseline) from an AE due to mAbs administered more than 4 weeks earlier.
    5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., <= Grade 1 or at baseline) from an AE due to a previously administered agent.
    6. Has a known additional malignancy within 2 years prior to enrollment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or curatively resected in situ cancers.
    7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided these brain metastases are stable (without evidence of progression by imaging over a period of at least 4 weeks and any neurologic symptoms have returned to baseline), they have no evidence of new or enlarging brain metastases (confirmed by imaging within 28 days of the first dose of trial treatment), and they are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
    8. Has known glioblastoma multiforme of the rainstem.
    9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
    10. Has an active infection requiring systemic therapy.
    11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial,or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
    12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
    14. Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or any other immune-modulating mAb (including ipilimumab and any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

    Refer to protocol for the rest of exclusion criteria.
    1. Sta partecipando ad uno studio e ricevendo una terapia in studio oppure ha partecipato ad uno studio condotto su un trattamento sperimentale ed ha ricevuto la terapia in studio o ha utilizzato un dispositivo sperimentale nelle 4 settimane che precedono la prima dose del trattamento.
    2. Presenta una diagnosi di immunodeficienza o sta assumendo una terapia con steroidi sistemici o altra forma di terapia immunosoppressiva nei 7 giorni precedenti la prima dose del trattamento sperimentale. L’uso di dosi fisiologiche di corticosteroidi può essere approvato previa consulenza con lo Sponsor.
    3. Presenta una malattia autoimmune in fase attiva che richiede un trattamento per via sistemica negli ultimi 2 anni (ossia, con impiego di agenti che modificano il decorso della malattia, corticosteroidi o farmaci immunosoppressori). La terapia di sostituzione (es. terapia di sostituzione con tiroxina, insulina o corticosteroidi fisiologici in caso di insufficienza surrenalica o ipofisaria ecc.) o il trattamento con farmaci (es. neomercazolo, carbamazolo, ecc) che diminuiscono la produzione di ormoni tiroidei da una ghiandola tiroidea iperfunzionante (es. nella malattia di Graves) non è considerata una forma di trattamento sistemico di una malattia autoimmune.
    4.Ha già assunto un anticorpo monoclonale (mAb) antitumorale nelle 4 settimane precedenti il Giorno 1 dello studio o ha avuto una ripresa non completa (ossia, Grado <= 1 o al basale) da AEs dovuti ai mAb somministrati più di 4 settimane prima.
    5. Si è già sottoposto a chemioterapia, terapia mirata con piccole molecole oppure a radioterapia nelle 2 settimane precedenti il Giorno 1 dello studio o ha avuto una ripresa non completa (ossia, Grado <= 1 o al basale) da AEs dovuti a un agente somministrato in precedenza.
    6. Presenta una neoplasia maligna aggiuntiva nota entro 2 anni precedenti l’arruolamento con l’eccezione del carcinoma cutaneo basocellulare e del carcinoma cutaneo squamocellulare trattati in modo curativo e/o del carcinoma cervicale in situ e/o del carcinoma mammario in situ asportati chirurgicamente.
    7. Presenta metastasi attive al sistema nervoso centrale (SNC) note e/o meningite carcinomatosa. I soggetti con metastasi cerebrali già trattate in precedenza possono partecipare purché le metastasi cerebrali siano stabili (senza evidenza di progressione all’esame radiologico nell’arco di un periodo di almeno 4 settimane e con qualsiasi sintomo neurologico tornato ai valori basali), purché non presentino evidenza di metastasi cerebrali di nuova insorgenza o in espansione (confermata mediante esame radiologico entro 28 giorni dalla prima dose del trattamento sperimentale) e non assumano steroidi da almeno 7 giorni prima del trattamento sperimentale. Questa eccezione non comprende la meningite carcinomatosa che è esclusa a prescindere dalla stabilità clinica.
    8. Presenta un glioblastoma multiforme al tronco encefalico.
    9. Presenta una storia di polmonite (non infettiva) che richiede trattamento con steroidi o polmonite attiva.
    10. Presenta un’infezione attiva che richiede una terapia per via sistemica.
    11. Presenta un’anamnesi o un riscontro ricorrente di qualsiasi condizione, terapia o anomalia nelle analisi di laboratorio che potrebbe inficiare i risultati della sperimentazione, interferire con la partecipazione del soggetto per tutta la durata della sperimentazione oppure non è nel miglior interesse del soggetto parteciparvi, a giudizio dello sperimentatore.
    12. Presenta disturbi psichiatrici o di abuso di sostanze noti che interferirebbero con la collaborazione agli obblighi posti dalla sperimentazione.
    13. È in gravidanza o allatta al seno, o prevede di concepire o generare figli nell’arco della durata stimata della sperimentazione, a partire dalla visita di screening fino a 120 giorni dopo l’ultima dose del trattamento sperimentale.

    Per i restanti criteri di esclusione fare riferimento al Protocollo
    E.5 End points
    E.5.1Primary end point(s)
    ORR based on RECIST 1.1 as assessed by independent central radiologic review.
    ORR determinata mediante revisione radiologica indipendente centralizzata, con valutazione di conferma secondo i criteri RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The trial incorporates an adaptive design in which multiple interim analyses may be performed. Results will be reviewed by the study team.
    The cutoffs for the three primary biomarker assays will be selected and specified before the first interim analysis. Details regarding the timing and conduct of the initial interim analysis will be further clarified in the sSAP. The planned sample size may be modified based on the interim results. The timing of additional interim analyses, the final analysis as
    well as the analysis plan will be documented in the sSAP. The sSAP will also be updated as the trial evolves. The primary endpoint of ORR will be used for all interim analyses with or without a confirmatory assessment; however, a confirmatory assessment is required for the final analysis.
    La sperimentaz incorpora un disegno adatt in cui poss essere eseg molteplici analisi ad interim. I risultati saran esami dal team dello studio. I valori cut-off per i dosaggi dei tre biomarcatori primari saran selezi e specificati prima della prima analisi ad interim. I dett riguard i tempi e lo svolgim dell’analisi ad interim iniziale saranno chiariti nel sSAP. La dimens del campion pianificata può essere modific in base ai risultati provv. I tempi delle analisi ad interim aggiunt, dell’analisi final, nonché il piano di analisi saran document nel sSAP. Il sSAP sarà inoltre aggiorn con l’evolversi della speriment.
    L’endpoint primario dell’ORR sarà utilizz per tutte le analisi ad interim con o senza la valutaz di conferma; tuttavia, una valutaz di conferma è richiesta per l’analisi finale.
    E.5.2Secondary end point(s)
    Safety and Tolerability
    Duration of response (DOR)
    Progression-free survival (PFS)
    Overall survival (OS)
    (PK) for the 200 mg iv Q3W fixed dosing regimen
    Sicurezza e tollerabilit¿
    Durata della risposta (DOR)
    Sopravvivenza senza progressione (PFS)
    Sopravvivenza globale (OS)
    PK per 200mg IV Q3W in regime di dose fissa
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy endpoints will be summarized at the time that the primary analysis is conducted; however, these secondary endpoints are
    not likely to be mature at that time.
    Gli endpoint di efficacia secondari verranno riassunti nel momento in cui verr¿ eseguita l¿analisi primaria; tuttavia, ¿ possibile che questi endpoint secondari non siano ancora maturi in quel momento.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    In aperto
    Open
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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
    Argentina
    Australia
    Brazil
    Canada
    Colombia
    Denmark
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    New Zealand
    Norway
    Philippines
    Russian Federation
    South Africa
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months6
    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: 675
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 675
    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 state54
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 500
    F.4.2.2In the whole clinical trial 1350
    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)
    At the end of treatment, each subject will be followed for 30 days to monitor for AEs and events of clinical interest; subjects will be monitored for serious AEs for 90 days after the end of treatment. Subjects who discontinue for reasons other than PD will have follow-up for disease status until experiencing PD, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed by telephone for overall survival.
    Al termine del tratt, sogg verrà seguito per 30 gg al fine di monitor eventi avversi e interesse clinico; sogg verran monit per eventi avversi seri per 90 gg dopo il termine del tratt. i sogg che interrom studio per ragioni diverse dalla progres della malattia, verran segu per valut lo status malattia fino a che non andran incontro a progres, inizieran 1 altro tratt per il tumore, ritirerran consenso, o saranno lost to follow-up. Tutti i sogg verran seg per tel per la valutaz della soprav compl.
    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 Decision2015-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-18
    P. End of Trial
    P.End of Trial StatusOngoing
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