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    Summary
    EudraCT Number:2020-004087-26
    Sponsor's Protocol Code Number:MK-3475-B61
    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:2021-05-20
    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 number2020-004087-26
    A.3Full title of the trial
    A Phase 2, Single-arm, Open-label Clinical Trial of Pembrolizumab Plus Lenvatinib in Participants with First-line Advanced/Metastatic Non-clear Cell Renal Cell Carcinoma (nccRCC) (KEYNOTE-B61)
    Studio clinico di fase II, a braccio singolo, in aperto, con pembrolizumab più lenvatinib come trattamento di prima linea in partecipanti con carcinoma a cellule renali non chiare (nccRCC) in stadio avanzato/metastatico (KEYNOTE-B61)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab + Lenvatinib for First Line Non-Clear Cell, Renal Cell Carcinoma
    Pembrolizumab più lenvatinib come trattamento di prima linea, carcinoma a cellule renali non chiare
    A.3.2Name or abbreviated title of the trial where available
    Pembro + Lenva for 1L nccRCC
    Pembro + Lenva per il trattamento di 1L del nccRCC
    A.4.1Sponsor's protocol code numberMK-3475-B61
    A.5.4Other Identifiers
    Name:INDNumber:122,753
    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.4.1Name of organisation providing supportEisai Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMSD Italia S.r.l.
    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 number00390636191371
    B.5.6E-mailpaola.fattore@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 nameLenvatinib
    D.3.2Product code [E7080]
    D.3.4Pharmaceutical form Capsule, hard
    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 INNLENVATINIB MESILATE
    D.3.9.1CAS number 857890-39-2
    D.3.9.2Current sponsor codeMK-7902
    D.3.9.3Other descriptive nameLENVATINIB MESILATE
    D.3.9.4EV Substance CodeSUB72971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 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 nameLenvatinib
    D.3.2Product code [E7080]
    D.3.4Pharmaceutical form Capsule, hard
    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 INNLENVATINIB MESILATE
    D.3.9.1CAS number 857890-39-2
    D.3.9.2Current sponsor codeMK-7902
    D.3.9.3Other descriptive nameLENVATINIB MESILATE
    D.3.9.4EV Substance CodeSUB72971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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 KEYTRUDA (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V. Num. 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 nameNA
    D.3.2Product code [NA]
    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
    Previously untreated advanced or metastatic nccRCC
    Carcinoma a cellule renali non chiare (nccRCC) in stadio avanzato/metastatico non trattato in precedenza
    E.1.1.1Medical condition in easily understood language
    Non-clear Cell Renal Cell Carcinoma
    Carcinoma a cellule renali non chiare
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10038409
    E.1.2Term Renal cell carcinoma NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To evaluate the objective response rate (ORR) of pembrolizumab + lenvatinib per response evaluation criteria in solid tumors 1.1 (RECIST 1.1) by blinded independent central review (BICR)
    - Valutare il tasso di risposta obiettiva (ORR) di pembrolizumab + lenvatinib secondo i criteri RECIST 1.1 mediante revisione centrale indipendente in cieco (BICR)
    E.2.2Secondary objectives of the trial
    1.To evaluate the duration of response (DOR) of pembrolizumab + lenvatinib in participants with a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by BICR
    2.To evaluate progression-free survival (PFS) per RECIST 1.1 by BICR in participants receiving pembrolizumab + lenvatinib
    3.To evaluate the overall survival (OS) of participants receiving pembrolizumab + lenvatinib
    4.To evaluate the clinical benefit ratio (CBR) of pembrolizumab + lenvatinib per RECIST 1.1 by BICR
    5.To evaluate the disease control rate (DCR) of pembrolizumab + lenvatinib per RECIST 1.1 by BICR
    6.To evaluate the safety of pembrolizumab + lenvatinib
    1. Valutare la durata della risposta (DOR) di pembrolizumab + lenvatinib nei partecipanti con risposta completa (CR) o risposta parziale (PR) confermata secondo i criteri RECIST 1.1 mediante BICR
    2. Valutare la sopravvivenza libera da progressione (PFS) secondo i criteri RECIST 1.1 mediante BICR nei partecipanti riceventi pembrolizumab + lenvatinib
    3. Valutare la sopravvivenza globale (OS) dei partecipanti riceventi pembrolizumab + lenvatinib
    4. Valutare il rapporto di beneficio clinico (CBR) di pembrolizumab + lenvatinib secondo i criteri RECIST 1.1 mediante BICR
    5. Valutare il tasso di controllo della malattia (DCR) di pembrolizumab + lenvatinib secondo i criteri RECIST 1.1 mediante BICR
    6. Valutare la sicurezza di pembrolizumab + lenvatinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Has a centrally confirmed diagnosis of non-clear cell RCC.
    2. Has locally advanced/metastatic disease (ie, Stage IV per the American Joint Committee on Cancer).
    3. Has received no prior systemic therapy for advanced nccRCC.
    4. Is male or female, from 18 years to 120 years of age inclusive, at the time of signing the informed consent.
    5. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 5 days after the last dose of study intervention)]:
    • 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.
    • Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    • Please note that 5 days after lenvatinib is stopped, if the male participant is on pembrolizumab only, no male contraception measures are needed.
    6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    • Is not a WOCBP
    OR
    • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    • A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours before the first dose of study intervention.
    • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    7. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study.
    For a full list of Inclusion criteria please refer to the Study Protocol.
    1. Presenta una diagnosi di RCC a cellule non chiare confermata a livello centrale.
    2. Presenta malattia localmente avanzata/metastatica (es. di stadio IV secondo la classificazione dell’American Joint Committee on Cancer)
    3. Non ha ricevuto alcuna terapia sistemica precedente per l’nccRCC avanzato.
    4. È di sesso maschile o femminile e ha un’età compresa tra 18 e 120 anni inclusi al momento della firma del consenso informato.
    5. I pazienti di sesso maschile sono idonei a partecipare se acconsentono a quanto segue durante il periodo di trattamento sperimentale e per almeno 5 giorni dopo l’ultima somministrazione di farmaco sperimentale:
    • Non avere rapporti eterosessuali come stile di vita preferito e abituale (astinenza a lungo termine e persistente) e accettare di astenersi da tali rapporti
    O
    • Acconsentire a utilizzare un metodo contraccettivo, a meno che non sia confermata l’azoospermia (in seguito a vasectomia o secondaria a cause mediche [Appendice 5]) come specificato di seguito:
    - Acconsentire a utilizzare un profilattico maschile e a far utilizzare alla partner un metodo contraccettivo aggiuntivo in caso di rapporti sessuali penetrativi vaginali con una donna in età fertile che non sia al momento incinta.
    • L’uso dei contraccettivi da parte dei pazienti di sesso maschile deve essere coerente con i regolamenti locali riguardanti i metodi contraccettivi per chi partecipa a studi clinici.
    • Si prega di notare che, 5 giorni dopo l’interruzione del trattamento con lenvatinib, se il partecipante di sesso maschile sta assumendo soltanto pembrolizumab non sono necessarie misure contraccettive da parte dei pazienti di sesso maschile.
    6. Le pazienti di sesso femminile sono idonee alla partecipazione se non sono in gravidanza o in allattamento, e se almeno una delle condizioni indicate di seguito risulta applicabile:
    • Non essere una donna in età fertile
    O
    • Essere una donna in età fertile e utilizzare un metodo contraccettivo altamente efficace (con un tasso di fallimento <1% all’anno), con scarsa dipendenza dell’utilizzatore, o non avere rapporti eterosessuali come stile di vita preferito e abituale (astinenza a lungo termine e persistente), secondo quanto descritto nell’Appendice [5], durante il periodo di trattamento sperimentale e per almeno 120 giorni dopo l’ultima dose di pembrolizumab o 30 giorni dopo l’ultima dose di lenvatinib, a seconda di quale evento si verifichi per ultimo. Lo sperimentatore deve valutare la possibilità di fallimento del metodo contraccettivo (mancata compliance, inizio recente) in relazione alla prima dose del trattamento sperimentale.
    • Le donne in età fertile devono avere esito negativo al test di gravidanza ad alta sensibilità ([eseguito su urine o siero] secondo quanto stabilito dai regolamenti locali) nelle 24 ore che precedono la prima dose del trattamento sperimentale.
    • Se non può essere confermata la negatività del test sulle urine (ad es. risultato ambiguo), è necessario eseguire un test di gravidanza su siero. In tali casi, la paziente deve essere esclusa
    dalla partecipazione se il test di gravidanza su siero risulta positivo.
    • Lo sperimentatore è responsabile dell’analisi dell’anamnesi medica, di quella mestruale e dell’attività sessuale recente finalizzata a ridurre il rischio di genotossicità di inclusione nello studio di una donna in gravidanza allo stadio iniziale non rilevata.
    • L’uso dei contraccettivi da parte delle pazienti di sesso femminile deve essere coerente con i regolamenti locali riguardanti i metodi contraccettivi per chi partecipa a studi clinici.
    7. Il partecipante (o il rappresentante legalmente riconosciuto, ove applicabile) fornisce il consenso/assenso informato documentato per lo studio.
    Per la lista completa dei criteri di inclusione fare riferimento al Protocollo di Studio
    E.4Principal exclusion criteria
    1. Has collecting duct histology.
    2. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study intervention. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    3. Has preexisting =Grade 3 gastrointestinal or non-gastrointestinal fistula.
    4. Has urine protein =1 g/24 hours.
    5. Has a left ventricular ejection fraction below the institutional (or local laboratory) normal range, as determined by multigated acquisition or echocardiogram.
    6. Has radiographic encasement or invasion of a major blood vessel, or of intratumoral cavitation.
    7. Has prolongation of QTcF interval to >480 msec.
    8. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
    9. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
    10. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
    11. Has had major surgery within 3 weeks prior to first dose of study intervention.
    12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
    13. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to allocation.
    14. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease.
    15. Has received a live or attenuated vaccine within 30 days before the first dose of study intervention.
    16. 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.
    17. 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 intervention.
    18. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
    19. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
    20. Has severe hypersensitivity (=Grade 3) to pembrolizumab, lenvatinib and/or any of their excipients.
    For a full list of Exclusion criteria please refer to the Study Protocol
    1. Presenta istologia del dotto collettore.
    2. Donne potenzialmente fertili con risultato positivo al test di gravidanza sulle urine nelle 24 ore precedenti la prima dose di trattamento sperimentale. Se non può essere confermata la negatività del test sulle urine, è necessario eseguire un test di gravidanza su siero. In tali casi, la paziente deve essere esclusa dalla partecipazione se il test di gravidanza su siero risulta positivo.
    3. Ha una fistola gastrointestinale o non gastrointestinale preesistente = Grado 3.
    4. Ha proteine delle urine =1 g/24 ore. .
    5. Ha una frazione di eiezione ventricolare sinistra al di sotto del range di normalità istituzionale (o del laboratorio locale), valutata mediante angiocardioscintigrafia o ecocardiogramma.
    6. Presenta evidenze radiografiche di inglobamento o invasione di un vaso sanguigno maggiore o di cavitazione intratumorale.
    8. Presenta malattia cardiovascolare clinicamente significativa entro 12 mesi dalla prima dose di trattamento sperimentale, inclusi insufficienza cardiaca congestizia di classe III o IV secondo la classificazione della New York Heart Association, angina instabile, infarto del miocardio, accidente cerebrovascolare, oppure aritmia cardiaca associata a instabilità emodinamica.
    9. Presenta malassorbimento gastrointestinale, anastomosi gastrointestinale o qualsiasi altra condizione che possa influenzare l’assorbimento di lenvatinib.
    10. Ha emottisi attiva (sangue di colore rosso vivo in una quantità pari almeno a 0,5 cucchiaini da tè) nelle 3 settimane precedenti la prima dose di trattamento sperimentale
    11. Ha ricevuto un intervento chirurgico importante nelle 3 settimane precedenti la prima dose del trattamento in studio.
    12. Ha ricevuto una terapia pregressa a base di un agente anti-PD-1, anti-PD-L1 o anti-PD-L2 o di un agente diretto contro un altro recettore delle cellule T co-inibitorio o stimolatorio (ad es. CTLA-4, OX-40, CD137).
    13. Ha ricevuto una precedente terapia antitumorale sistemica tra cui gli agenti sperimentali nelle 4 settimane precedenti l’assegnazione.
    14. Ha ricevuto precedente radioterapia nelle 2 settimane precedenti l’inizio del trattamento sperimentale. I partecipanti devono essersi ristabiliti da tutte le tossicità correlate alla radioterapia, non necessitare di corticosteroidi e non presentare polmonite da radiazioni. È consentito un wash-out di 1 settimana per la radioterapia palliativa (=2 settimane di radioterapia) su malattia non SNC.
    15. È stato vaccinato con vaccino vivo o attenuato nei 30 giorni precedenti la prima dose del trattamento sperimentale.
    16. Partecipazione attuale o pregressa a uno studio su un farmaco sperimentale o utilizzo di un dispositivo sperimentale nelle 4 settimane precedenti la prima dose del trattamento in studio.
    17. Presenta una diagnosi di immunodeficienza o trattamento cronico con steroidi sistemici (in dosi superiori a 10 mg/die di un equivalente del prednisone) o qualsiasi altra forma di terapia immunosoppressiva nei 7 giorni precedenti la prima dose del trattamento sperimentale.
    18. Presenta un ulteriore tumore maligno noto che è progredito o ha richiesto un trattamento attivo negli ultimi 3 anni.
    19. Presenta metastasi al SNC attive note e/o meningite carcinomatosa. I partecipanti con metastasi cerebrali trattate precedentemente possono partecipare, purché siano radiologicamente stabili (ossia, senza evidenza di progressione) da almeno 4 settimane agli esami di imaging ripetuti (si noti che gli esami di imaging ripetuti devono essere eseguiti durante lo screening dello studio), siano clinicamente stabili e non richiedano il trattamento con steroidi almeno nei 14 giorni precedenti la prima dose di trattamento sperimentale.
    20. Ha ipersensibilità grave (grado =3) a pembrolizumab, lenvatinib e/o a uno qualsiasi degli eccipienti.
    Per la lista completa dei criteri di esclusione fare riferimento al Protocollo di Studio
    E.5 End points
    E.5.1Primary end point(s)
    1.Objective Response Rate (ORR) is defined as the percentage of participants with a complete response (CR) or partial response (PR) per response evaluation criteria in solid tumors 1.1 (RECIST 1.1) by blinded independent central review (BICR).
    1.Il tasso di risposta obiettiva (ORR) è definito come la percentuale di partecipanti con una risposta completa (CR) o una risposta parziale (PR) secondo i criteri RECIST 1.1
    da revisione centrale indipendente in cieco (BICR).
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.Up to approximately 2 years
    1. Fino a circa 2 anni
    E.5.2Secondary end point(s)
    2. Progression-free Survival (PFS) is defined as the time from the date of first dose to the first documented progressive disease (PD) per RECIST 1.1 by BICR or death from any cause, whichever occurs first.; 3.Overall Survival (OS) is defined as the time from date of first dose until death from any cause.; 4.Clinical Benefit Ratio (CBR) is defined as the percentage of participants who achieved CR, PR, or stable disease (SD) for at least 6 months per RECIST 1.1 by BICR.; 5. Disease Control Rate (DCR) is defined as the percentage of participants who achieved CR, PR or SD per RECIST 1.1 by BICR.; 7.Participants Who Discontinued Study Medication Due to an AE.; 1.Duration of Response (DOR) is defined for participants who demonstrate confirmed CR or PR as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.; 6. Participants Who Experienced One or More Adverse Events (AEs)
    2. Sopravvivenza libera da progressione (PFS) è definita come il tempo dalla prima dose alla prima PD documentata o alla morte per qualsiasi causa, in base all’evento che si verifica per primo; 3. Sopravvivenza globale (OS) è definita come il tempo dalla prima dose al decesso per qualsiasi causa; 4. Rapporto di beneficio clinico (CBR) è definito come la percentuale di partecipanti che raggiungono le condizioni di CR, PR o malattia stabile (SD) confermate per almeno 6
    mesi secondo i criteri RECIST 1.1 mediante BICR; 5. Tasso di controllo della malattia (DCR) è definito come la percentuale di partecipanti che raggiungono le condizioni di CR, PR, o SD confermate secondo i criteri RECIST 1.1 mediante BICR; 7. Partecipanti che hanno interrotto lo studio dovuto a AE; 1. Durata della risposta (DOR) è definita come il tempo dalla prima evidenza documentata di CR o PR fino alla progressione di malattia o alla morte per qualsiasi causa, in base all’evento che si verifica per primo; 6. Partecipanti che hanno avuto uno o più eventi avversi (AEs)
    E.5.2.1Timepoint(s) of evaluation of this end point
    2. Up to approximately 2 years; 3.Up to approximately 2 years; 4.Up to approximately 2 years; 5.Up to approximately 2 years; 7.Up to approximately 2 years; 1.Up to approximately 2 years; 6.Up to approximately 2 years
    2. Fino a circa 2 anni; 3. Fino a circa 2 anni; 4. Fino a circa 2 anni; 5. Fino a circa 2 anni; 7. Fino a circa 2 anni; 1. Fino a circa 2 anni; 6. Fino a circa 2 anni
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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
    Studio in aperto
    Open-label Study
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    Canada
    China
    France
    Hungary
    Italy
    Korea, Republic of
    Poland
    Russian Federation
    Spain
    Turkey
    Ukraine
    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 years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 52
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 152
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    nessun trattamento
    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 Decision2021-02-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-17
    P. End of Trial
    P.End of Trial StatusOngoing
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