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    Summary
    EudraCT Number:2014-004842-92
    Sponsor's Protocol Code Number:SECOMBIT
    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:2016-10-18
    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 number2014-004842-92
    A.3Full title of the trial
    A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy (ipilimumab/nivolumab) and combo target therapy (LGX818/MEK162) in patients with metastatic melanoma and BRAF mutation
    Studio prospettico di fase II randomizzato a tre bracci mirato a valutare il miglior approccio sequenziale con il trattamento immunoterapico combinato (ipilimumab/nivolumab) e la terapia target combinata (LGX818/MEK162) in pazienti affetti da melanoma metastatico portatori della mutazione BRAF
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy (ipilimumab/nivolumab) and combo target therapy (LGX818/MEK162) in patients with metastatic melanoma and BRAF mutation
    Studio prospettico di fase II randomizzato a tre bracci mirato a valutare il miglior approccio sequenziale con il trattamento immunoterapico combinato (ipilimumab/nivolumab) e la terapia target combinata (LGX818/MEK162) in pazienti affetti da melanoma metastatico portatori della mutazione BRAF
    A.3.2Name or abbreviated title of the trial where available
    SECOMBIT
    SECOMBIT
    A.4.1Sponsor's protocol code numberSECOMBIT
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02631447
    A.5.4Other Identifiers
    Name:SECOMBITNumber:SECOMBIT
    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 SponsorFONDAZIONE MELANOMA ONLUS
    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 supportAzienda Farmaceutica: Bristol Mayers Squibb S.r.l. - Italia
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportAzienda Farmaceutica: Array BioPharma Inc - Stati Uniti d'America
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione Melanoma ONLUS
    B.5.2Functional name of contact pointStudy Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressVia Mariano Semmola
    B.5.3.2Town/ cityNapoli
    B.5.3.3Post code80131
    B.5.3.4CountryItaly
    B.5.4Telephone number0815903841
    B.5.5Fax number0815903841
    B.5.6E-mailcurvietto.ma@gmail.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 nameNivolumab - OPDIVO
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 YERVOY - 5 MG/ML - CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO (VETRO) - 40 ML 1 FLACONCINO
    D.2.1.1.2Name of the Marketing Authorisation holderBRISTOL-MYERS SQUIBB PHARMA EEIG
    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 nameIpilimumab - YERVOY
    D.3.2Product code BMS-734016
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 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 nameEncorafenib
    D.3.2Product code LGX818
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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: 4
    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 nameBinimetinib
    D.3.2Product code MEK162
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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
    Metastatic melanoma and BRAF mutation
    Melanoma metastatico portatori della mutazione BRAF
    E.1.1.1Medical condition in easily understood language
    Metastatic melanoma and BRAF mutation
    Melanoma metastatico portatori della mutazione BRAF
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    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 define the best sequencing combination treatment in primary efficacy variable overall survival (OS).
    Definire la migliore combinazione di trattamenti in sequenza in relazione alla Overall Survival (OS), variabile primaria di efficia.
    E.2.2Secondary objectives of the trial
    To evaluate the effects of the two sequencing combination treatments on:
     Total PFS;
     Percentage of patients alive at 2 and 3 years;
     Best overall response rate (BORR);
     Duration of response (DoR);
     Toxicity of the investigational medicinal products (IMPs)
     Quality of life and general health status
    Valutare gli effetti delle due combinazioni di trattamenti in sequenza in termini di:
     Sopravivvenza globale libera da malattia (–Total PFS);
     Percentuale di pazienti vivi a 2 e 3 anni;
     Miglior tasso di risposta globale (BORR);
     Durata della Risposta (DoR);
     Tossicità dei prodotti medicinali sperimentali (IMPs);
     Qualità della vita e stato di salute generale
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    SECOMBIT

    ”Sequential Combo Immuno and Target therapy (SECOMBIT) study”

    “A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy (ipilimumab/nivolumab) and combo target therapy (LGX818/MEK162) in patients with metastatic melanoma and BRAF mutation”
    The objective of the biomarkers ancillary study (to be conducted in a subgroup of approximately 80-90 patients) is to focus on understanding mechanisms of action/resistance. In particular, the ancillarystudy will inform how to sequence targeted RAF/MEK agents with immunotherapy agents (i.e. ipilumumab and nivolumab) in melanoma and will be hypothesis-generating only.
    Quality of life and general health status defined by:
    o Health-related quality of life (HRQoL), by means of the 30-item European Organisation for Research and Treatment of Care quality of life questionnaire (EORTC QLQC30);
    o General health status, by means of the European Quality of Life 5-Dimensions(EQ-5D) questionnaire;
    o Impairment of work productivity and activity, by means of the Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire;
    v. 1.0
    data 22/10/2015
    SECOMBIT
    “Sequential Combo Immuno and Target therapy (SECOMBIT) study”

    “Studio prospettico di fase II randomizzato a tre bracci mirato a valutare il miglior approccio sequenziale con il trattamento immunoterapico combinato (ipilimumab/nivolumab) e la terapia target combinata (LGX818/MEK162) in pazienti affetti da melanoma metastatico portatori della mutazione BRAF”
    L’obiettivo dello studio ancillare sui biomarcatori è quello di approfondire la conoscenza sui meccanismi di azione/resistenza. In particolare lo studio ancillare:
    • Fornirà informazioni su come sequenziare gli agenti targeted RAF/MEK con gli agenti immunoterapici (es: ipilimumab e nivolumab) in pazienti affetti da melanoma;
    • Sarà unicamente volto a generare ipotesi.
    Qualità della vita e stato di salute generale definito da:
    o Qualità della vita correlate alla salute (HRQoL), tramite un questionario composto da 30 domande formulato dall’ European Organisation for Research and Treatment of Care (EORTC QLQC30);
    o Stato di salute generale, definito dal questionario European Quality of Life 5-Dimensions(EQ-5D);
    o Compromissione della produttività e attività lavorativa, attraverso il questionario Work Productivity and Activity Impairment: General Health (WPAI:GH).

    v. 1.0
    data 22/10/2015
    E.3Principal inclusion criteria
    1) Patients of either sex aged ≥ 18 years;
    2) Histologically confirmed stage III (unresectable) or stage IV melanoma with the BRAF V600 mutation. Patients with mucosal melanoma (but not those with ocular melanoma) are eligible for study participation;
    3) Treatment naïve patients. As previous systemic treatmtne for melanoma only interferon is permitted (note that prior adjuvant melanoma therapy is permitted if completed at least 6 weeks prior to randomization, and all related adverse events have either returned to baseline or stabilized).
    4) Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria;
    5) Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment;
    6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (appendix 7);
    7) Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. An archive sample is mandatory at the screening visit; however, a fresh sample would be preferable;
    8) Female subjects of childbearing potential must have a negative serum pregnancy test result at Baseline and must practice a reliable method of contraception for the total study duration plus 23 weeks (i.e. 30 days plus the time required for nivolumab to undergo five half lives) after the last dose of nivolumab and ipilimumab;
    9) Men who are sexually active with women of childbearing potential must practice a reliable method of contraception for the total study duration plus 31 weeks (i.e. 80 days plus the time required for nivolumab to undergo five half lives) after the last dose of nivolumab and ipilimumab;
    10) Adequate bone marrow haematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L AND platelet count ≥ 100 x 109/L AND haemoglobin ≥ 9 g/dL;
    11) Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) AND aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 X ULN (< 5 x ULN if liver metastases);
    12) Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥ 50 mL/min in females (calculated according to Cockroft-Gault formula);
    13) Serum calcium levels, international normalised ratio (INR) and partial thromboplastin time were within normal limits;
    14) Life expectancy of at least 3 months;
    15) Ability to understand study-related patient information and provision of written informed consent for participation in the study.
    1) Pazienti di entrambi i sessi, età ≥ 18 anni;
    2) Pazienti affetti da melanoma stadio III (non resecabile) o stadio IV portatori di mutazione BRAF V600 confermato istologicamente. Pazienti affetti da melanoma mucosale sono elegibili per lo studio (ad eccezione di quelli affetti da melanoma oculare);
    3) Pazienti naïve al trattamento. E’ permessa la somministrazione di solo interferone come terapia adiuvante per il melanoma (precedenti terapie adiuvanti per il melanoma sono permesse se completate da almeno 6 settimane precedenti la randomizzazione, e se tutti gli eventi avversi correlati sono tornati al valore del basale o stabilizzati);
    4) Malattia misurabile accertata da Tomografia Computerizzata (CT) o Risonanza Magnetica (MRI) sulla base dei criteri RECIST 1.1.;
    5) Presenza della mutazione BRAF V600E o V600K nel tessuto tumorale precedente all’arruolamento;
    6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) compreso tra 0 e 1;
    7) Un campione di tessuto tumorale da un sito metastatico o non resecabile deve essere fornito per l’analisi dei biomarcatori. Un campione di archivio è mandatorio alla visita di screening, tuttavia, un campione di tessuro fresco sarebbe preferibile;
    8) Soggetti di sesso femminile potenzilmente fertili devono avere la conferma di un test di gravidanza negativo al basale e devono utilizzare metodi di contraccezione affidabili durante tutto il corso dello studio più 23 settimane (ovvero 30 giorni sommati al tempo richiesto da nivolumab per superare cinque emivite) dall’ultima somministrazione di nivolumab e ipilimumab;
    9) Pazienti di sesso maschile che sono sessualmente attivi con donne potenzialmenti fertili devono utilizzare metodi di contraccezione adeguati per tutta la durata dello studio più 31 settimane (ovvero 80 giorni più il tempo richiesto da nivolumab per superare cinque emivite) dall'ultima somministrazione di nivolumab e ipilimumab;
    10) Adeguata funzione ematologica del midollo osseo: conta assoluta dei neutrofili (ANC) ≥ 1,5 x 109/L E conta piastrinica ≥ 100 x 109/L E emoglobina ≥ 9 g/dL;
    11) Adeguata funzione epatica: bilirubina totale ≤ 1.5 x limite superiore dei valori normali (ULN) E aspartato aminotrasferasi (AST)/ alanino aminotrasferasi (ALT) ≤ 2.5 x ULN (< 5 X ULN in presenza di metastasi epatiche);
    12) Adeguata funzionalità renale: creatinina sierica ≤ 1,5 mg/dL OPPURE clearance della creatinina ≥ 60 mL/min negli uomini e ≥ 50 mL/min nelle donne (calcolata in accordo alla formula di Cockroft-Gault);
    13) Livelli di calcio sierico, rapporto internazionale normalizzato (INR) e tempo di tromboplastina parziale entro i limiti di normalità;
    14) Aspettativa di vita di almeno 3 mesi;
    15) Capacità di capire le informazioni al paziente studio-correlate e volontà di sottoscrivere un consenso informato firmato per la partecipazione allo studio.
    E.4Principal exclusion criteria
    1) Active brain metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration;
    2) Subjects with active, known or suspected autoimmune disease;
    3) Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment;
    4) Prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody;
    5) Female subjects who are pregnant (positive pregnancy test), breast-feeding, or who are of childbearing potential and not practicing a reliable method of birth control;
    6) Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study;
    7) Patients with a history of cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy (Past or present evidence of rethinophaty central serous retinopathy - CSR -, occlusion of retinal - RVOo retinal degenerative disease) or ophthalmopathy, which according to the ophthalmologic evaluation at baseline could be considered a risk factor for CSR / RVO ( eg. cupping of the optic disc, visual field defect, intraocular pressure - (eg: central IOP - > 21 mmHg).;
    8) History of Gilbert's syndrome;
    9) Inability to regularly access centre facilities for logistical or other reasons;
    10) History of poor co-operation, non-compliance with medical treatment, or unreliability;
    11) Participation in any interventional drug or medical device study within 30 days prior to treatment start.
    12) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
    13) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
    1) Metastasi cerebrali attive. I soggetti con metastasi cerebrali sono elegibili se sono stati trattati e in assenza di evidenza, tramite risonanza magnetica, di progressione per almeno 8 settimane dalla fine del trattamento e nei 28 giorni precedenti la prima somministrazione di farmaco sperimentale. Non ci deve essere necessità di somministrazione di dosi immunosoppressive di corticosteridi sistemici (> 10 mg/giorno equivalenti al prednisone) per almeno 2 settimane precedenti la somministrazione di farmaco sperimentale;
    2) Soggetti con malattia autoimmune attiva, conosciuta o sospetta;
    3) Soggetti affetti da condizione clinica che richieda trattamenti sistemici con corticosteroidi (>10 mg al giorno di equivalenti a prednisone) o altri trattamenti immunosoppressivi nei 14 giorni precedenti il trattamento;
    4) Precedente trattamento con anticorpi anti-recettore1 di morte programmata (PD-1), anti-liganti1 di morte programmata (PD-L1), anti –PD-L2, o qualsiasi anticorpo anti-citotossico T linfocitario associato all’ antigene 4 (anti-CTLA-4):
    5) Soggetti di sesso femminile che sono in gravidanza (test di gravidanza positivo), in allattamento o potenzialmente feritili che non utilizzano un metodo contraccettivo affidabile:
    6) Evidenza di malattia sistemica severa e non controllata o qualsiasi condizione concomitante che, secondo l’opinione del medico Sperimentatore, renda non auspicabile la partecipazione del paziente nello studio, comprometta la compliance al protocollo o che possa interferire con i risultati dello studio;
    7) Pazienti con storia di malattia cardiovascolare o polmonare interstiziale ed evidenza o rischio di occlusione della vena retinale o retinopatia centrale sierosa;
    8) Storia di sindorme di Gilbert;
    9) Impossibilità di potersi recare regolamente al centro clinico per motivi logistici o altro;
    10) Storia di poca cooperazione, non-compliance ai trattamenti e inaffidabilità;
    11) Partecipazione ad altri studi interventistici su farmaco o dispositivo medico nei 30 giorni precedenti l’inizio del trattamento sperimentale;
    12) Positività per l’antigene di supercie del virus dell’epatite B (HBV sAg) o dell’ acido ribonucleico del virus dell’epatite C (anticorpo HCV) che indichi infezione acuta o cronica;
    13) Storia nota di positività al virus di immunodeficienza umana (HIV) o sindrome acquisita di immunodeficienza (AIDS);
    E.5 End points
    E.5.1Primary end point(s)
    OS is primary endpoint of the study. OS will be calculated as the time from the date of randomization until the date of death from any cause.
    L’endpoint primario dello studio è l’Overall Survival (OS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Any patient not know to have died at the time of data analysis will be censored at the time of the last recorded date on which the patient was know to be alive.
    L’OS verrà calcolata come il tempo dalla data di randomizzazione fino alla data di decesso per qualsiasi causa. Per i pazienti di cui non si hanno informazioni sul decesso al tempo dell’analisi dei dati dello studio saranno inclusi i dati fino all’ultima data in cui il paziente era noto essere vivo.
    E.5.2Secondary end point(s)
    Total Progression Free Survival – PFS
    Percentage of patients alive at 2 and 3 years;
    Best overall response rate (BORR)
    Duration of response (DoR)
    Biological markers (biomarkers ancillary study);
    Quality of life and General health status  Health-related quality of life (HRQoL), by means of the 30-item European Organisation for Research and Treatment of Care quality of life questionnaire (EORTC QLQC30);  General health status, by means of the European Quality of Life 5-Dimensions (EQ-5D) questionnaire;
    Safety endpoints • Toxicity of the IMPs (NCI CTC-AE Version 4.03 criteria); • Adverse events (AEs) and serious adverse events (SAEs) • Vital signs (weight, BMI, heart rate, blood pressure); • Laboratory safety parameters (haematology, blood chemistry, urinalysis).
    Sopravvivenza globale libera da malattia (Total Progression Free Survival – PFS)
    Percentuale di pazienti vivi a 2 e 3 anni;
    Miglior tasso di risposta globale al trattamento (Best overall response rate- BORR)
    Durata della risposta (Duration of response – DoR)
    Marcatori biologici (studio ancillare sui biomarcatori);
    Qualità della vita e stato di salute  Qualità della vita correlata alla salute (HRQoL), tramite un questionario composto da 30 domande formulato dall’ European Organisation for Research and Treatment of Care (EORTC QLQC30);  Stato di salute generale, mediante il questionario European Quality of Life 5-Dimensions (EQ-5D);
    Endpoints di sicurezza Tossicità degli IMPs (criteri NCI CTC-AE Versione 4.03); • Eventi avversi (AEs) ed eventi avversi seri (SAEs); • Segni vitali (peso, BMI, frequenza cardiaca, pressione sanguigna); • Parametri di sicurezza del laboratorio (ematologia, biochimica, analisi delle urine)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints of evaluation will be calculated from the date of randomization until the date of the second progression (i.e. the progression to second treatment); any progression or death will be considered as an event if patient cannot complete treatment sequence;2^ and 3^ years from randomization;From randomization until end of study;Timepoints of evaluation will be calculated as the time from the date of first documented response (CR or PR) until the date of the first documented progression or death due to underlying cancer. If the patient with a CR or PR has no progression or death due to underlying cancer, the patient will be censored at the time of last adequate tumor assessment;End of study;At the end of the study;During the study
    Il tempo di rilevazione parte dalla data di randomizzazione fino alla data della 2^ progressione (ovvero la progressione del 2^ trattamento); ogni progressione di malattia o decesso sarà considerato come un evento se il paziente non potrà completare la sequenza del trattamento;2^e 3^anno dalla randomizzazione;Dalla data di randomizzazione fino alla conclusione dello studio;Il tempo di rilevazione sarà calcolato come il tempo che intercorre dalla data della 1^risposta documentata(CR o PR)fino alla data della prima progressione documentata o decesso causato dalla malattia.Se il paziente con una CR o PR non ha progressione o morte a causa della malattia,il paziente verrà censurato alla data dell’ultima valutazione tumorale adeguata;Fine studio;A fine studio;Durante tutto il corso dello studi
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 EEA24
    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 No
    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
    Treatment duration will be until PD (2 years estimated). It is expected that the study will start (First Patient First Visit Date) on Febrary 2016, the recruitment will end (Last Patient First Visit) on September 2017, and the Study will end (Last Patient Last Visit) on. September 2020. The date of study end is dependent on the clinical course of the disease and may therefore occur earlier than indicated.
    Il trattamento sperimentale continuerà fino a Progressione di malattia (PD). Si prevede l'inizio dello studio (First Patient First visit) a Febbraio 2016, il reclutamento terminerà (Last Patient Last Visit) a Settembre 2020. La data di conclusione della sperimentazione dipende dal decorso clinico della malattia che può essere anticipato rispetto a quanto previsto.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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: 115
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 115
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 230
    F.4.2.2In the whole clinical trial 230
    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)
    Treatment plans for treatment or care after a subject has ended his/her participation in the trial will follow clinical practice
    I programmi per il trattamento o l'assistenza per i soggetti al termine della loro partecipazione allo studio seguono la normale pratica clinica
    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 Decision2016-06-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-20
    P. End of Trial
    P.End of Trial StatusOngoing
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