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    Summary
    EudraCT Number:2021-000743-41
    Sponsor's Protocol Code Number:W00090GE302/EORTC-1902-MG
    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:2021-10-18
    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 number2021-000743-41
    A.3Full title of the trial
    Adjuvant encorafenib & binimetinib vs. placebo in resected stage II BRAF V600E/K mutated melanoma: a randomized triple-blind Phase III Study in
    collaboration with the EORTC Melanoma Group.
    Encorafenib e binimetinib adiuvanti rispetto al placebo nel melanoma in stadio II, resecato, con mutazione BRAF V600E/K: studio randomizzato di fase III in triplo cieco in collaborazione con l’EORTC Melanoma Group
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Encorafenib used with binimetinib versus placebo in BRAF mutant stage II melanoma after surgery to evaluate the efficacy and safety in preventing
    melanoma recurrence
    Encorafenib utilizzato con binimetinib rispetto al placebo nel melanoma in stadio II con mutazione BRAF dopo l'intervento chirurgico per valutare l'efficacia e la sicurezza nella prevenzione recidiva del melanoma
    A.3.2Name or abbreviated title of the trial where available
    Not available
    Non disponibile
    A.4.1Sponsor's protocol code numberW00090GE302/EORTC-1902-MG
    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 SponsorPIERRE FABRE MéDICAMENT
    B.1.3.4CountryFrance
    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 supportPierre Fabre Médicament
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPierre Fabre Médicament
    B.5.2Functional name of contact pointIsabelle Klauck
    B.5.3 Address:
    B.5.3.1Street Address45, Place Abel Gance
    B.5.3.2Town/ cityBoulogne
    B.5.3.3Post code92100
    B.5.3.4CountryFrance
    B.5.4Telephone number+33149108018
    B.5.5Fax number000000
    B.5.6E-mailisabelle.klauck@pierre-fabre.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 Yes
    D.2.1.1.1Trade name Braftovi
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    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 nameEncorafenib
    D.3.2Product code [W0090]
    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 INNENCORAFENIB
    D.3.9.1CAS number 1269440-17-6
    D.3.9.2Current sponsor codeW0090
    D.3.9.4EV Substance CodeSUB177218
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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 Yes
    D.2.1.1.1Trade name Mektovi
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    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 namebinimetinib
    D.3.2Product code [W0074]
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNBINIMETINIB
    D.3.9.1CAS number 606143-89-9
    D.3.9.2Current sponsor codeW0074
    D.3.9.4EV Substance CodeSUB179942
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Resected BRAF V600E/K stage II melanoma
    Melanoma asportato BRAF V600E/K stadio II
    E.1.1.1Medical condition in easily understood language
    Stage II melanoma with mutation in the V600E/K gene after surgery
    Melanoma in stadio II con mutazione nel gene V600E/K dopo intervento chirurgico
    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 10053571
    E.1.2Term Melanoma
    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 prospectively assess whether treatment with encorafenib and binimetinib prolongs recurrence-free survival as compared to placebo in resected pT2b-4bN0M0 BRAF V600E/K melanoma participants.
    Valutare prospetticamente se il trattamento con encorafenib e binimetinib prolunga la sopravvivenza libera da recidiva rispetto al placebo in partecipanti con melanoma pT2b-4bN0M0 BRAF V600E/K resecato.
    E.2.2Secondary objectives of the trial
    1.To prospectively assess whether treatment with encorafenib and binimetinib prolongs distant metastasis-free survival (DMFS) as compared to placebo.
    2.To prospectively assess whether treatment with encorafenib and binimetinib prolongs overall survival (OS) as compared to placebo.
    3.To characterize the safety and tolerability.
    4.To compare the patient-reported health-related (HRQoL) between the two arms during the treatment duration and after treatment completion.
    1. Valutare prospetticamente se il trattamento con encorafenib e binimetinib prolunga la sopravvivenza libera da metastasi a distanza (DMFS) rispetto al placebo.
    2. Valutare prospetticamente se il trattamento con encorafenib e binimetinib prolunga la sopravvivenza complessiva (OS) rispetto al placebo.
    3. Caratterizzare la sicurezza e la tollerabilità.
    4. Confrontare la salute riferita dal paziente (HRQoL) tra i due bracci durante la durata del trattamento e dopo il completamento del trattamento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Molecular pre-screening
    1. Before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations ;
    2. Male or female = 18 years of age;
    3. Surgically resected, with tumor free margins, and histologically/pathologically confirmed new diagnosis of stage II (pT2bpT4bN0) cutaneous melanoma per AJCC 8th edition;
    4. Sentinel node (SN) staged node negative (pN0);
    5. Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of melanoma;

    Screening
    1. Melanoma determined locally to be V600E/K mutation-positive. Note: only PCR and NGS-based local assay results will be acceptable;
    2. Participant still free of disease as evidenced by the required baseline imaging and physical/dermatological assessments performed within 6 weeks from the randomization (Day 1);
    3. Before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations;
    4. Randomization within 12 weeks from SN biopsy;
    5. Able to provide a sufficient amount of representative tumor specimen (diagnostic biopsy) for retrospective central testing of BRAFV600E/K mutation status. FFPE tumor tissue block or a minimum of 10 slides, optimally up to 15 slides;
    6. Recovered from definitive surgery (e.g. complete wound healing, no uncontrolled wound infections or indwelling drains);
    7. ECOG performance status of 0 or 1;
    8. Adequate bone marrow function:
    i. Absolute neutrophil count (ANC) = 1.5 x 1000000000/L
    ii. Platelets = 100 x1000000000 /L
    iii. Hemoglobin = 9.0 g/dL
    9. Adequate renal function:
    Serum creatinine = 1.5 × ULN; or calculated creatinine clearance = 50 mL/min by Cockcroft-Gault formula;
    10. Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits.
    11. Adequate hepatic function:
    i. Serum total bilirubin = 1.5 x ULN and < 2 mg/dL
    ii. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) = 2.5 x ULN
    12. Adequate cardiac function:
    i. Left ventricular ejection fraction (LVEF) = 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram
    ii. Mean triplicate QT interval corrected for heart rate according to Fridericia's formula (QTcF) value = 480 msec and no history of QT syndrome
    13. Negative serum ß-HCG test (female patient of childbearing potential only) performed within 3 days prior to Day 1;
    14. Participants of childbearing / reproductive potential should use adequate birth control measures (see Appendix 4, section 10.4.2):
    Female participants are either postmenopausal for at least 1 year, surgically sterile for at least 6 weeks or must agree to take appropriate precautions to avoid pregnancy.
    Male participants must agree to take appropriate precautions to avoid
    fathering a child.
    Pre-screening molecolare
    1. Prima di qualsiasi attività correlata allo studio, deve essere fornito il consenso informato scritto in conformità alle indicazioni del Consiglio internazionale sull’armonizzazione (ICH)/alla Buona pratica clinica (GCP) e alle normative nazionali/locali;
    2. Soggetti di sesso maschile o femminile di età = 18 anni;
    3. Chirurgicamente resecati, con margini liberi da tumore, e
    nuova diagnosi istologicamente/patologicamente confermata di melanoma cutaneo di stadio II (pT2bpT4bN0) secondo AJCC 8ª edizione;
    4. Linfonodo sentinella (SN) rappresentato da linfonodo negativo (pN0);
    5. Biopsia del linfonodo sentinella (SN) entro 14 settimane dalla diagnosi iniziale di melanoma;
    Screening
    1. Melanoma determinato localmente come positivo alla mutazione V600E/K. Nota: saranno accettabili solo i risultati ottenuti mediante analisi locali basate su test PCR e NGS;
    2. Il/la partecipante è ancora libero/a dalla malattia come evidenziato dalla diagnostica per immagini al basale e dalle valutazioni fisiche/dermatologiche previste ed eseguite entro 6 settimane dalla randomizzazione (Giorno 1);
    3. Prima di qualsiasi attività correlata allo studio, deve essere fornito il consenso informato scritto in conformità alle indicazioni del Consiglio internazionale sull’armonizzazione (ICH)/alla Buona pratica clinica (GCP) e alle normative nazionali/locali;
    4. Randomizzazione entro 12 settimane dalla biopsia SN;
    5. Capacità di fornire una quantità sufficiente di campione tumorale rappresentativo (biopsia diagnostica) per l’analisi retrospettiva centrale dello stato mutazionale di BRAFV600E/K. Blocco di tessuto tumorale FFPE o un minimo di 10 vetrini, preferibilmente fino a 15 vetrini;
    6. Recupero da un intervento chirurgico definitivo (ad esempio guarigione completa della ferita, nessuna infezione non controllata della ferita o drenaggi permanenti); 7. Stato delle prestazioni ECOG pari a 0 o 1; 8. Adeguata funzionalità del midollo osseo:
    i. Conta assoluta dei neutrofili (ANC) =1,5 x 1000000000/L ii. Piastrine =100 x 1000000000/L iii. Emoglobina =9,0 g/dl; 9. Adeguata funzionalità renale:
    creatinina sierica = 1,5 × ULN, oppure clearance della creatinina calcolata = 50 ml/min secondo la formula di Cockcroft-Gault;
    10. Adeguati livelli degli elettroliti, definiti come livelli sierici di potassio e magnesio entro i limiti della norma dell’istituto.
    11. Adeguata funzionalità epatica:
    i. Bilirubina sierica totale = 1,5 x ULN e < 2 mg/dl
    ii. Alanina aminotransferasi (ALT) e/o aspartato aminotransferasi
    (AST) = 2,5 x ULN
    12. Adeguata funzionalità cardiaca:
    i. Frazione di eiezione ventricolare sinistra (FEVS) = 50% determinata da una
    scansione di acquisizione multigate (MUGA) o ecocardiogramma
    ii. Valore medio dell’intervallo QT misurato in tre intervalli corretto per la frequenza cardiaca secondo la formula di Fridericia (QTcF) = 480 msec e nessuna anamnesi di sindrome del QT
    13. Test della ß-HCG sierico negativo (solo per le pazienti di sesso femminile fertili) eseguito nei 3 giorni precedenti il Giorno 1;
    14. I partecipanti fertili/con potenziale riproduttivo devono adottare adeguate misure di controllo delle nascite (vedere Appendice 4, sezione 10.4.2): Le partecipanti di sesso femminile devono essere in post-menopausa da almeno 1 anno, chirurgicamente sterili da almeno 6 settimane oppure devono acconsentire ad adottare le dovute precauzioni per evitare una gravidanza.
    I partecipanti di sesso maschile devono acconsentire ad adottare le dovute precauzioni al fine di evitare di concepire un figlio.
    E.4Principal exclusion criteria
    Molecular pre-screening
    1. Unknown ulceration status;
    2. Uveal and mucosal melanoma;
    3. Clinically apparent metastases (N+/M1);
    4. Microsatellites, satellites and/or in-transit metastases;
    5. Local (scar) recurrences.
    Screening
    1. Breast feeding women;
    2. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
    3. History of thromboembolic or cerebrovascular events = 12 weeks prior to randomization;
    i. Note 1: Thromboembolic or cerebrovascular events include stroke, transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e massive or sub-massive) deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis;

    ii. Note 2: Participants with thromboembolic events related to indwelling catheters or other procedures may be enrolled;
    4. Previous or concurrent malignancy for the past 3 years (must be free from disease for at least 3 years). Except for non-melanoma skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and any in situ
    cancer;
    5.Participants with a prior cancer associated with RAS mutation;
    6. Previous treatment for melanoma beyond complete surgical resection (any prior systemic anticancer therapy; prior radiotherapy);
    7. Hypersensitivity to the study drugs or to any of the excipients;
    8. Participants with severe lactose intolerance (e.g Rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption);
    9.Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
    iii. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) = 6 months prior to randomization;
    iv. Congestive heart failure requiring treatment (New York Heart Association Grade = 2);
    v. Uncontrolled hypertension defined as persistent systolic blood pressure = 150 mmHg or diastolic blood pressure = 100 mmHg despite optimal therapy;
    vi. Presence of clinically significant cardiac arrhythmias including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia (stable controlled atrial fibrillation or paroxysmal supraventricular tachycardia is accepted);
    10. Neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
    11. Non-infectious pneumonitis and Interstitial Lung Disease;
    12. Positive SARs-CoV-2 or variants of SARs-CoV2 RT-PCR test at screening or suspected to be infected with SARs-CoV2 or variants of SARsCoV2 with confirmation pending;
    13. Known history of a positive serology for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), known history of a positive serology for active hepatitis B, and/or
    hepatitis C;
    14. Unable to ingest or digest tablets and capsules. This can be caused by any impaired gastrointestinal function or disease, such as for example: ulcerative diseases, malabsorption syndrome, small bowel
    resection, ileus, etc. Or any condition causing uncontrolled nausea, vomiting or diarrhea;
    15. Presence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before randomization in the trial;
    Please refer to the protocol for a complete list of exclusion criteria.
    Italiano Pre-screening molecolare
    1. Stato di ulcerazione non noto;
    2. Melanoma uveale e mucoso;
    3. Metastasi clinicamente evidenti (N+/M1);
    4. Microsatelliti, satelliti e/o metastasi in transito;
    5. Recidive locali (cicatrici).
    Screening
    1. Donne che allattano al seno;
    2. Anamnesi o evidenza attuale di occlusione venosa retinica (RVO) o fattori di rischio attuali per RVO (ad es. glaucoma non controllato o ipertensione oculare, anamnesi di iperviscosità o sindromi da ipercoagulabilità);
    3. Anamnesi di eventi tromboembolici o cerebrovascolari = 12 settimane prima della randomizzazione;
    i. Nota 1: Gli eventi tromboembolici o cerebrovascolari comprendono ictus, attacchi ischemici transitori, accidenti cerebrovascolari, trombosi venosa profonda emodinamicamente significativa (ovvero massiva o sub-massiva), embolia polmonare, aneurisma aortico che richiede riparazione chirurgica o trombosi arteriosa periferica recente;

    ii. Nota 2: Possono essere arruolati partecipanti con eventi tromboembolici correlati ad altre procedure o cateteri permanenti;
    4. Tumore maligno pregresso o concomitante negli ultimi 3 anni (deve essere libero dalla malattia da almeno 3 anni). Fatta eccezione per il carcinoma cutaneo non melanoma (carcinomi a cellule basali o carcinomi a cellule squamose) e qualsiasi tumore in situ;
    5. Partecipanti con un precedente tumore associato a mutazione RAS;
    6. Precedente trattamento per il melanoma oltre la resezione chirurgica completa
    (qualsiasi precedente terapia antitumorale sistemica; precedente radioterapia);
    7. Ipersensibilità ai farmaci dello studio o a uno qualsiasi degli eccipienti; 8. Partecipanti con grave intolleranza al lattosio (ad es., rari problemi ereditari di intolleranza al galattosio, deficit totale di lattasi o malassorbimento di glucosio/galattosio);
    9. Funzione cardiovascolare compromessa o malattie cardiovascolari clinicamente significative, incluse una qualsiasi delle seguenti: iii. Anamnesi di infarto miocardico acuto, sindromi coronariche acute (comprese angina instabile, innesto di bypass coronarico, angioplastica coronarica o stent) = 6 mesi prima della randomizzazione; iv. Insufficienza cardiaca congestizia che richiede trattamento
    (di grado = 2 secondo la New York Heart Association);
    v. Ipertensione non controllata, definita come pressione sanguigna sistolica persistente = 150 mmHg o pressione sanguigna diastolica = 100 mmHg nonostante terapia ottimale;
    vi. Presenza di aritmie cardiache clinicamente significative tra cui fibrillazione atriale non controllata o tachicardia parossistica sopraventricolare non controllata (è consentita la fibrillazione atriale stabile controllata o tachicardia parossistica sopraventricolare);
    10. Disturbi neuromuscolari associati a CK > ULN (ad es. miopatie infiammatorie, distrofia muscolare, sclerosi laterale amiotrofica, atrofia muscolare spinale);
    11. Polmonite non infettiva e malattia polmonare interstiziale; 12. Positività a SARs-CoV-2 o a varianti del SARs-CoV2 tramite test RT-PCR allo screening, oppure sospetta infezione da SARs-CoV2 o varianti di
    SARs-CoV2 in attesa di conferma;
    13. Anamnesi nota di sierologia positiva al virus dell’immunodeficienza umana (HIV) o sindrome da immunodeficienza acquisita (AIDS) nota, anamnesi nota di sierologia positiva per epatite B attiva e/o epatite C;
    14. Incapacità di ingerire o digerire compresse e capsule. Ciò può essere causato da una qualsiasi compromissione della funzionalità o da una patologia gastrointestinale, come ad esempio: malattie ulcerative, sindrome da malassorbimento, resezione dell’intestino tenue, dell’ileo, ecc. Oppure qualsiasi condizione che causi nausea, vomito o diarrea non controllati;
    Per una lista completa dei criteri di inclusione far riferimento al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Recurrence-free survival (RFS)
    Sopravvivenza libera da recidiva (RFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Approximately 4.7 years from the accrual of the first patient.The longterm evaluation will take place 10 years from the randomization of the last patient.
    Circa 4,7 anni dall’arruolamento del primo paziente. La valutazione a lungo termine avrà luogo 10 anni dopo la randomizzazione dell’ultimo paziente.
    E.5.2Secondary end point(s)
    1.Distant metastasis-free survival (DMFS)
    2.Overall survival (OS)
    3.•Severity of adverse events and SAEs on-study graded according to NCI CTCAE Version 5.0
    •Changes from baseline and worst value on-study for clinical safety laboratory assessments, physical examinations, vital signs, ECGs, ECHO, dermatological examinations, ophthalmic examinations and ECOG performance status
    •Incidence of dose interruptions, dose modifications and discontinuation due to AEs and incidence of AEs requiring additional therapy
    4. •The change in the HRQoL from baseline to the average of the scores during the treatment
    •The change in the HRQoL from baseline to week 48
    1. Sopravvivenza libera da metastasi a distanza (DMFS) 2. Sopravvivenza complessiva (OS)
    3. •La gravità di eventi avversi e SAE (eventi avversi seri) durante lo studio classificati in base alla versione 5.0 dei criteri NCI CTCAE.
    •Variazioni rispetto al basale e valore peggiore durante lo studio per valutazioni cliniche di laboratorio per la sicurezza, esami obiettivi, segni vitali, ECG, ECO, esami dermatologici, esami oftalmici e stato di validità ECOG
    •Incidenza delle interruzioni della dose, delle modifiche della dose e della sospensione del trattamento a causa di EA e incidenza di EA che richiedono un’ulteriore terapia
    4. • Variazione della HRQoL dal basale alla media dei punteggi durante il trattamento
    •Variazione della HRQoL dal basale alla Settimana 48
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. 6.9 years from first patient in
    2.At the time of the DMFS analysis (6.9 years from first patient in)
    3.At the time of the RFS analysis (4.7 years from first patient in)
    4.At the time of the RFS analysis (4.7 years from first patient in)
    1. 6,9 anni dal primo paziente in entrata
    2. Al momento dell’analisi DMFS (6,9 anni dal primo paziente in entrata) 3. Al momento dell’analisi RFS (4,7 anni dal primo paziente in entrata) 4. Al momento dell’analisi RFS (4,7 anni dal primo paziente in entrata)
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Triplo cieco
    Triple Blind
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA79
    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
    Austria
    Belgium
    Denmark
    France
    Germany
    Italy
    Netherlands
    New Zealand
    Norway
    Poland
    Spain
    Sweden
    Switzerland
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of study is defined as the point when all patients have had the opportunity to be followed for 10 years from study entry. If the last participant discontinues the follow-up for one of the following reasons: withdrawal of consent, loss to follow-up, or death, the end of study participation is defined as the time point when one of these events occurred for the last participant.
    La fine dello studio è definita come il punto in cui tutti i pazienti avranno avuto l’opportunità di essere seguiti per 10 anni a partire dall’ingresso nello studio. Se l’ultimo partecipante interrompe il follow-up per uno dei seguenti motivi: ritiro del consenso, perdita al follow-up o decesso, la conclusione della partecipazione allo studio è definita come il punto temporale in cui si è verificato uno di questi eventi per l’ultimo partecipante.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years13
    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 years13
    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: 720
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 180
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 699
    F.4.2.2In the whole clinical trial 900
    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)
    Patients will be treated as per standard of care depending on the disease stage at recurrence/relapse.
    I pazienti saranno trattati secondo lo standard di cura in base allo stadio della malattia al momento della recidiva/ricaduta.
    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 Decision2021-07-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-21
    P. End of Trial
    P.End of Trial StatusOngoing
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