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    Summary
    EudraCT Number:2018-001441-14
    Sponsor's Protocol Code Number:IFOM-CPT002/2018/PO001
    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:2021-01-14
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-001441-14
    A.3Full title of the trial
    PEMBROLIZUMAB IN MMR-PROFICIENT METASTATIC COLORECTAL CANCER PHARMACOLOGICALLY PRIMED TO TRIGGER DYNAMIC HYPERMUTATION STATUS
    PEMBROLIZUMAB IN PAZIENTI CON CANCRO DEL COLON RETTO METASTATICO CON SISTEMA DI “MISMATCH REPAIR” INTATTO DOPO INDUZIONE FARMACOLOGICA DI IPERMUTABILITÀ
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II trial in extended RAS- mutated metastatic colorectal patients refractory to standard treatments.
    Studio clinico di fase II in pazienti con cancro del colon retto metastatico con mutazione di un gene della famiglia “RAS” resistente alle terapie standard.
    A.3.2Name or abbreviated title of the trial where available
    THE ARETHUSA TRIAL
    Studio ARETHUSA
    A.4.1Sponsor's protocol code numberIFOM-CPT002/2018/PO001
    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 SponsorIFOM - Istituto FIRC di Oncologia Molecolare - Milano
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIFOM - Istituto FIRC di Oncologia Molecolare - Milano
    B.5.2Functional name of contact pointPrecision Oncology Unit
    B.5.3 Address:
    B.5.3.1Street AddressVia Adamello 16
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20139
    B.5.3.4CountryItaly
    B.5.4Telephone number02574303862
    B.5.6E-mailsilvia.marsoni@ifom.eu
    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.3.9.3Other descriptive nameHumanized IgG4 PD-1 blocking 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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name KEYTRUDA (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameKEYTRUDA (pembrolizumab, MK-3475)
    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: 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 TEMOZOLOMIDE SUN
    D.2.1.1.2Name of the Marketing Authorisation holderSUN PHARMACEUTICAL INDUSTRIES (EUROPE) B.V.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nametemozolomide
    D.3.2Product code [temozolomide]
    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 INNTemozolomide
    D.3.9.1CAS number 85622-93-1
    D.3.9.2Current sponsor codeTEMOZOLOMIDE
    D.3.9.3Other descriptive nameoral alkylating agent
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 250
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    RAS mutated metastatic colorectal cancer
    cancro metastatico al colon retto in pazienti con mutazioni RAS
    E.1.1.1Medical condition in easily understood language
    metastatic colorectal cancer
    cancro metastatico al colon retto
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal cancer metastatic
    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
    To assess the objective response rate of pembrolizumab in metastatic MMR proficient, extended RAS mutated CRC patients who have failed standard therapies, with MGMT-negative tumors treated with TMZ, given with the intent of increasing the mutational load of their tumors (cohort P).
    Valutare il tasso di risposta effettiva (Objective Response Rate, ORR) di pembrolizumab nei pazienti con mCRC mutati in RAS, MMR-P, in cui le terapie standard hanno fallito, con MGMT-metilato e che sono stati trattati con TMZ con l’intenzione di aumentare il carico mutazionale del tumore (coorte P).
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    To assess the objective response rate in MMR deficient patients (cohort D)
    identified during the MMR screening.
    • To assess the Progression Free Survival (PFS) and Overall Survival (OS) both
    P and D cohorts patients.
    • To assess the safety and tolerability of pembrolizumab after TMZ-priming
    therapy (cohort P).
    • To assess the safety and tolerability of pembrolizumab (cohort D).
    Translational Objectives:
    • To validate the assessment of mutational load in plasma using the tissue
    mutational load as ‘gold’ standard.
    • To assess the relationship between selected immune biomarkers in archival
    and/or fresh tumor tissue and blood with response to pembrolizumab.
    • To compare these immunomarkers profiles prior and after TMZ in cohort P
    patients, and prior and after pembrolizumab treatment in all patients (cohort D
    and P).
    • To assess the relationship of RAS status in MMR deficient patients (cohort D)
    with response to Pembrolizumab.
    Obiettivi secondari:
    • Valutare ORR nei pazienti MMR-D (coorte D) identificati durante loscreening per MMR.
    • Valutare la PFS e la OS in entrambe le coorti di pazienti (P and C).
    • Valutare la sicurezza e la tollerabilità di pembrolizumab dopo la terapia di induzione con TMZ (coorte P).
    • Valutare la sicurezza e la tollerabilità di pembrolizumab (coorte D).
    Obiettivi traslazionali:
    • Validare la misura del carico mutazionale nel plasma utilizzando quello misurato nel tessuto come “gold standard”.
    • Valutare la correlazione tra l’espressione di marcatori biologici immunitari misurati su tessuto (fresco o da archivio) e nel sangue con la risposta al
    pembrolizumab.
    • Confrontare l’espressione di questi immunomarcatori prima e dopo terapia con TMZ nei pazienti appartenenti alla coorte P e prima e dopo trattamento con
    pembrolizumab in tutti i pazienti (coorti D e P).
    • Valutare la correlazione tra lo stato di RAS e la risposta al Pembrolizumab neipazienti MMR-D
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Fase di selezione (SCREENING):
    Diagnosi di mCRC confermata istologicamente.
    Documentata mutazione “RAS extended” nei campioni di archivio.
    Stato della condizione secondo ECOG (performance status) 0-1.
    Firma del consenso informato della fase SCREENING.
    Comprensione e accettazione della necessità di essere sottoposti a due biopsie tumorali se eleggibile per la fase di PRIMING dello studio.
    Età = 18 anni.
    Disponibilità di tutti i blocchetti FFPE (tumore primario e o metastasi) o di almeno 20 vetrini (tumore primario e/o metastasi). I blocchetti fissati in formalina o paraffinati (FFPE) devono essere preferiti ai vetrini.
    Funzionalità d’organo normali.
    Fase di PRIMING:
    1. Fulfilment of all the SCREENING inclusion criteria;
    2. PRIMING informed consent signed;
    3. Confirming the willingness to undergo two tumor biopsies,
    4. Acceptance that, if the mutational load determination is unfeasible for
    technical reasons (not enough tissue, substandard test performance, etc.),
    access to TRIAL phase will not be possible.
    5. Imaging documented failure of previous standard CRC therapies including
    fluoropyrimidine, oxaliplatin, irinotecan plus or minus antiangiogenics
    agents (Bevacizumab, Aflibercept, Regorafenib, others).
    6. At least one measurable tumor lesion as per RECIST v1.1. Lesions in
    previously irradiated areas or those that have received other loco-regional
    therapies (i.e. percutaneous ablation) should not be considered measurable
    unless there is clear documented evidence of progression of the lesion since
    therapy. Imaging must be performed maximum within 28 days prior to
    enrolment.
    7. ECOG performance status 0 or 1;
    8. Following results in the SCREENING Phase tests:
    • Proficient MMR status assessed by IHC or MSI-Low status defined by
    PCR (Bethesda panel);
    • Negative score for the MGMT protein expression IHC test;
    • Positive score for the MGMT promoter methylation performed on Tissue.
    9. Women with childbearing potential should complete a pregnancy test and
    be willing to use highly effective contraceptive methods.
    10. Normal organ functions.
    Fase di TRIAL:
    1. Fulfilment of all the SCREENING inclusion criteria and Deficient MMR
    status (IHC) or MSI-High status (PCR) (cohort D only).
    2. Fulfilment of all the SCREENING and PRIMING inclusion criteria (cohort
    P only).
    3. TRIAL Phase informed consent signed (both cohorts).
    4. Imaging documented PD to TMZ (cohort P only).
    5. A mutational load value > 20 mutations/MB at TMZ-ML assay (cohort P
    only).
    6. Imaging documented failure of previous standard CRC therapies including
    fluoropyrimidine, oxaliplatin, irinotecan plus or minus targeted agents
    (Bevacizumab, Aflibercept, Regorafenib, Cetuximab, Panitumumab,
    others) (cohort D only).
    7. At least one measurable tumor lesion as per RECIST v1.1. Lesions in
    previously irradiated areas or those that have received other loco-regional
    therapies (i.e. percutaneous ablation) should not be considered measurable
    unless there is clear documented evidence of progression of the lesion since
    therapy. Imaging must be performed maximum within 28 days prior to
    enrolment (both cohorts).
    8. Woman with childbearing potential should complete a pregnancy test and
    be willing to use highly effective contraceptive methods (both cohorts).
    9. Normal organ functions. Blood specimens must be collected within 10 days
    prior to the start of study treatment (both cohorts).
    Fase di selezione (SCREENING):
    1. Diagnosi di mCRC confermata istologicamente.
    2. Documentata mutazione “RAS extended” nei campioni di archivio (solo
    coorte P).
    3. Stato della condizione secondo ECOG (performance status) 0-1.
    4. Firma del consenso informato della fase SCREENING.
    5. Comprensione e accettazione della necessità di essere sottoposti a due biopsie
    tumorali se eleggibile per la fase di PRIMING dello studio.
    6. Età = 18 anni.
    7. Disponibilità di tutti i blocchetti FFPE (tumore primario e o metastasi) o di
    almeno 20 vetrini (tumore primario e/o metastasi). I blocchetti fissati in
    formalina o paraffinati (FFPE) devono essere preferiti ai vetrini.
    8. Funzionalità d’organo normali.
    Fase di PRIMING:
    1. Aderenza a tutti i criteri di inclusione della fase di selezione (SCREENING).
    2. Firma del consenso informato della fase di PRIMING.
    3. Conferma della volontà di andare incontro a due biopsie tumorali.
    4. Accettazione dell’assunto che, se la determinazione del carico mutazionale
    dovesse essere irrealizzabile per ragioni tecniche (tessuto insufficiente,
    condizioni sotto lo standard del test, ecc.), non sarà possibile accedere alla
    fase TRIAL.
    5. Documentazione radiologica che attesti l’insuccesso delle precedenti terapie
    standard per CRC che possono includere: fluoropirimidina, oxaliplatino,
    irinotecano con o senza agenti antiangiogenici (Bevacizumab, Aflibercept,
    Regorafenib, altri).
    6. Almeno una lesione tumorale misurabile secondo RECIST v1.1. Lesioni in
    aree precedentemente irradiate o quelle che hanno ricevuto terapie locoregionali
    (ad esempio ablazione percutanea) non saranno considerate
    misurabili fino a quando non verrà documentata una evidenza di progressione
    della lesione dalla terapia. Le indagini radiologiche devono essere state
    eseguite entro i 28 giorni precedenti all’arruolamento.
    7. Stato della condizione secondo ECOG (performance status) 0-1.
    8. Seguenti risultati nei test della fase di selezione (SCREENING):
    9. Stato di MMR valutato per immunoistochimica o stato MSI-Low valutato
    tramite PCR (Pannello Bethesda).
    10. Espressione negativa della proteina di MGMT in immunoistochimica.
    11. Metilazione del promotore di MGMT positiva su tessuto.
    12. Donne in età fertile dovranno eseguire un test di gravidanza e dovranno
    accettare di utilizzare metodi contracettivi altamente efficaci.
    13. Funzionalità d’organo normali.
    Fase di TRIAL:
    1. Aderenza a tutti i criteri di inclusione della fase di selezione (SCREENING)
    e stato MMR-D o MSI-High (solo coorte D).
    2. Aderenza a tutti i criteri di inclusione delle fasi di selezione e priming
    (SCREENING e PRIMING) (solo coorte P).
    3. Firma del consenso informato della fase TRIAL (entrambe le coorti).
    4. Immagini radiologiche che documentino progressione a TMZ (solo coorte
    P).
    5. Valore di carico mutazionale > 20 mutazioni/MB misurato su tessuto dopo
    progressione a TMZ (solo coorte P).
    6. Documentazione radiologica che attesti l’insuccesso delle precedenti terapie
    standard per CRC che possono includere: fluoropirimidina, oxaliplatino,
    irinotecano con o senza agenti antiangiogenici (Bevacizumab, Aflibercept,
    Regorafenib, altri) (solo coorte D).
    7. Almeno una lesione tumorale misurabile secondo RECIST v1.1. Lesioni in
    aree precedentemente irradiate o quelle che hanno ricevuto terapie locoregionali
    (ad esempio ablazione percutanea) non saranno considerate
    misurabili fino a quando non verrà documentata una evidenza di progressione della lesione dalla terapia. Le indagini radiologiche devono essere state
    eseguite entro i 28 giorni precedenti all’arruolamento (entrambe le coorti).
    8. Donne in età fertile dovranno eseguire un test di gravidanza e dovranno
    accettare di utilizzare metodi contracettivi altamente efficaci (entrambe le
    coorti).
    9. Funzionalità d’organo normali. I campioni ematici devono essere raccolti
    entro i 10 giorni precedenti l’inizio del trattamento correlato allo studio
    (entrambe le coorti).
    E.4Principal exclusion criteria
    A woman of child bearing potential who has a positive serum pregnancy test within 72 hours prior to allocation; Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137);Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to enrollment;Has received prior radiotherapy within 2 weeks of start of study treatment (with Pembrolizumab); Has received a live vaccine within 30 days prior to the first dose of study drug; 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 treatment; Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug; Has a known additional malignancy that is progressing or has required active treatment within the past 3 years; Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. 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 treatment; Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients; Has severe hypersensitivity (=Grade 3) to temozolomide and/or any of its excipients; Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis; Has an active infection requiring systemic therapy; Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required; Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority; Has a known history of active TB (Bacillus Tuberculosis); Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator; Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial; Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
    Donne in età fertile con test di gravidanza positivo entro 72 ore prima dell’allocazione
    Precedente terapia con agenti anti-PD-1, anti-PD-L1, anti-PD-L2 o con agenti diretti contro altri stimolatori o co-inibitori del recettore dei linfociti T (es., CTLA-4, OX-40, CD137)
    Precedente terapia antineoplastica sistemica nella 4 settimane [possono essere considerati intervalli di tempo più ridotti per inibitori di chinasi o altri farmaci a breve emivita] precedenti all’arruolamento
    Precedente radioterapia entro due settimane dall’inizio del trattamento con Pembrolizumab
    Terapia con vaccini vivi entro 30 giorni dalla prima dose del farmaco di studio
    Partecipazione a studi con altre terapie sperimentali (inclusi dispositivi) entro 4 settimane dalla prima dose del farmaco di studio
    Pazienti con diagnosi di immunodeficienza o che stanno ricevendo terapia steroidea sistemica (con dose superiore a 10 mg/die di prednisone) o qualsiasi altra forma di terapia immunosoppressiva entro 7 giorni dalla prima dose del farmaco di studio
    Nota ulteriore neoplasia che è in progressione o ha richiesto trattamento attivo nei 3 anni precedenti.
    Pazienti con metastasi sintomatiche del sistema nervoso centrale (SNC) e/o meningite carcinomatosa
    Severa ipersensibilità (=Grado 3) al pembrolizumab e/o a qualsiasi suo eccipiente
    Severa ipersensibilità (=Grado 3) alla temozolomide e/o a qualsiasi suo eccipiente
    Pazienti con patologie autoimmuni attive che hanno richiesto trattamenti sistemici negli ultimi 2 anni
    Anamnesi positiva per polmonite (non infettiva) che ha richiesto steroidi o evidenza attuale di polmonite
    Evidenza attuale di infezione attiva che richiede terapia sistemica
    Anamnesi positiva per virus dell’immunodeficienza (HIV)
    Anamnesi positiva per epatite B
    Anamnesi positiva per tubercolosi (Bacillus Tuberculosis) attiva
    Evidenza attuale o pregressa di qualsiasi condizione, terapia o alterazione degli esami di laboratorio che, secondo l’opinione dello sperimentatore, possano interferire con l’interpretazione dei risultati della sperimentazione, con la partecipazione del paziente per l’intera durata dello studio o nel caso in cui non sia nell’interesse del paziente partecipare alla sperimentazione
    Anamnesi positiva per patologie psichiatriche o abuso di sostante che potrebbero interferire con la collaborazione del paziente ai requisiti dello studio
    Pazienti in gravidanza o in allattamento o con intenzione di intraprendere una gravidanza, entro la durata prevista dello studio, partendo dalla visita di screening sino a 120 giorni dopo l’ultima dose del trattamento di studio
    E.5 End points
    E.5.1Primary end point(s)
    ORR a pembrolizumab nella coorte P in accordo con il sistema di valutazione RECIST
    ORR a pembrolizumab nella coorte P in accordo con il sistema di valutazione RECIST
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 9 weeks during trial phae (treatment with pembrolizumab) and every 8 weeks during post-treatment follow-up phase
    Ogni 9 settimane durante la fase di trial (trattamento con pembrolizumab) ed ogni 8 settimane nella fase di follow-up post trattamento
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    ORR to pembrolizumab in cohort D according to RECIST.
    PFS and OS in both cohorts P and D.
    Safety and tolerability according to CTCAE version 4.03.
    Translational Endpoints:
    Validation of tumor mutational load assessment in plasma.
    Expression of immune markers and their correlation with response to temozolomide and pembrolizumab.
    ORR to pembrolizumab in RAS and non-RAS mutant stratified cohort D according to RECIST.
    Endpoints secondari:
    ORR a pembrolizumab nella coorte D in accordo con il sistema di valutazione RECIST.
    PFS e OS in entrambe le coorti P e D.
    Sicurezza e tollerabilità secondo CTCAE versione 4.03.
    Endpoints traslazionali:
    Validazione della valutazione del carico mutazionale misurato nel plasma.
    Espressione dei marcatori immunologici e loro correlazione con la risposta alla temozolomide e al pembrolizumab.
    ORR a pembrolizumab nella coorte D stratificata per pazienti RAS e non-RAS
    mutati in accordo con il sistema di valutazione RECIST.
    E.5.2.1Timepoint(s) of evaluation of this end point
    the whole study
    durante tutto lo studio
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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
    2 coorti
    2-cohort
    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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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 years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    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: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 34
    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 state101
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 101
    F.4.2.2In the whole clinical trial 101
    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)
    clinical standard therapies
    terapie da pratica clinica standard
    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 Decision2018-10-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-05
    P. End of Trial
    P.End of Trial StatusOngoing
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