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    The EU Clinical Trials Register currently displays   43976   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2012-001676-11
    Sponsor's Protocol Code Number:FIL_MIRO
    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:2014-09-03
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-001676-11
    A.3Full title of the trial
    "MIRO" study (Molecularly Oriented Immuno-radio-therapy): a multicenter phase II trail for the treatment on molecular basis of stage I / II Follicular Lymphoma with local radiotherapy with / without Ofatumumab
    Studio “MIRO” (Molecularly Immuno-radio-therapy Oriented): studio multicentrico di fase II per il trattamento su base molecolare dei Linfomi Follicolari stadio I/II con radioterapia locale con/senza Ofatumumab
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    "MIRO" study (Molecularly Oriented Immuno-radio-therapy): a multicenter phase II trail for the treatment on molecular basis of stage I / II Follicular Lymphoma with local radiotherapy with / without Ofatumumab
    Studio “MIRO” (Molecularly Immuno-radio-therapy Oriented): studio multicentrico di fase II per il trattamento su base molecolare dei Linfomi Follicolari stadio I/II con radioterapia locale con/senza Ofatumumab
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberFIL_MIRO
    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.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 supportGLAXO SMITH KLINE SPA
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.2Functional name of contact pointSECRETARY
    B.5.3 Address:
    B.5.3.1Street AddressVIA VENEZIA 16
    B.5.3.2Town/ cityALESSANDRIA
    B.5.3.3Post code15121
    B.5.4Telephone number00390131206261
    B.5.5Fax number00390131263455
    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. name ARZERRA
    D. of the Marketing Authorisation holderGlaxo Group Ltd 980 Great West Road Brentford Middlesex TW8 9GS - UK
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameOFATUMUMAB
    D.3.4Pharmaceutical form Concentrate for 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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    D. medicinal product typeMonoclonal antibody
    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
    Stage I/II Follicular Lymphoma
    Trattamento di pazienti con linfoma follicolare (FL) di stadio I/IIA.
    E.1.1.1Medical condition in easily understood language
    Stage I/II Follicular Lymphoma
    Trattamento di pazienti con linfoma follicolare (FL) di stadio I/IIA.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the proportion of patients obtaining disappearance of Bcl-2-IgH rearranged cells in peripheral blood and/or bone marrow by PCR, after treatment with Ofatumumab.
    Valutare la proporzione di pazienti che ottiene la negativizzazione del riarrangiamento Bcl-2-IgH alla PCR qualitativa e quantitativa dopo il trattamento con Ofatumumab.
    E.2.2Secondary objectives of the trial
    To evaluate clinical response rate, relapse-free survival (RFS) and progression-free survival (PFS) in patients treated with local radiotherapy and molecularly–based Ofatumumab consolidation and/or retreatment; these objectives will be defined by clinical and instrumental procedures, according to Cheson criteria.

    To evaluate the role of quantitative PCR determination of basal Bcl-2-IgH rearranged cells in PB and BM in predicting the probability of negativization after local radiotherapy and the probability of relapse.
    Valutare la percentuale di risposta clinica, sopravvivenza libera da recidiva (RFS) e sopravvivenza libera da progressione (PFS) nei pazienti trattati con radioterapia locale e trattamento molecolare di consolidamento e / o di ritrattamento con Ofatumumab; questi obiettivi saranno definiti da procedure cliniche e strumentali secondo i criteri di Cheson.
    Valutare il ruolo della PCR quantitativa nella determinazione al basale delle cellule riarrangiate Bcl-2-IgH in PB e in BM nel predire la probabilità di negativizzazione dopo la radioterapia locale e la probabilità di recidiva.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically confirmed follicular lymphoma grade I-IIIa;
    • Stage IA or IIA (no more than 2 contiguous nodal regions) non bulky (<7 cm);
    • FLIPI <2, FLIPI2 <2;
    • Previously untreated;
    • Age ≥ 18;
    • Informed consent;
    • Staging with PET-CT, bone marrow biopsy;
    • Qualitative/quantitative PCR basal evaluation of Bcl-2/IgH rearranged cells in peripheral blood and bone marrow.
    • Linfoma follicolare di grado I-IIIa confermato istologicamente;
    • Stadio IA o IIA (non più di 2 siti linfonodali contigui) non bulky (<7 cm);
    • Pazienti non trattati in precedenza;
    • FLIPI < 2, FLIPI2 < 2;
    • Età ≥ 18;
    • Firma del consenso informato;
    • Stadiazione con PET-CT, biopsia del midollo osseo;
    • Valutazione qualitativa / quantitativa della PCR basale delle cellule Bcl-2/IgH positive nel sangue periferico e midollo osseo.
    E.4Principal exclusion criteria
    • Follicular lymphoma grade IIIb;
    • Stage greater than II with more than 2 nodal sites and/or B symptoms and/or bulky disease (>7 cm);
    • FLIPI >2, FLIPI2 >2;
    • Age < 18;
    • Previous treatments for non-Hodgkin’s lymphoma;
    • Dementia;
    • Impossibility to subscribe the informed consent;
    • Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones or stable chronic liver disease per investigator assessment)
    • Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study
    • Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
    • Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C.
    • History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae
    • Known HIV positive
    • Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to start of treatment, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.
    • Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
    • Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a quantitative HBV-DNA test will be performed and if positive the subject will be excluded. Patients with HBcAb positivity and negative HBV DNA should be prophilactically treated with oral Lamivudine (100 mg /day) in case of treatment with Ofatumumab, to be prosecuted 12 months after treatment.
    • Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HCV-RNA on the same sample to confirm the result;
    • Hematologic and blood chemistry esclusion criteria:
    platelets <50 x 109/L;
    neutrophils <1.0 x 109/L;
    creatinine >2.0 times upper normal limit;
    total bilirubin >1.5 times upper normal limit;
    ALT >2.5 times upper normal limit;
    alkaline phosphatase >2.5 times upper normal limit.
    • Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening.
    Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence
    • Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.
    • Linfoma follicolare di grado III b;
    • Stadio superiore al II con più di 2 siti nodali e / o sintomi B e / o malattia bulky (> 7 cm);
    • FLIPI >2, FLIPI2 >2;
    • Età <18;
    • Pazienti precedentemente trattati per il linfoma non-Hodgkin;
    • Dementia
    • Impossibilità a sottoscrivere il consenso informato
    • Soggetti che hanno in corso malattia epatica attiva o biliare (ad eccezione dei pazienti con sindrome di Gilbert, calcoli biliari asintomatici, metastasi epatiche o malattie stabili croniche del fegato secondo valutazione dello sperimentatore);
    • Pazienti trattati con qualsiasi sostanza farmaceutica non commercializzata o con terapia sperimentale con emivita di 5 o 4 settimane come periodo più lungo precedenti l'arruolamento, o che attualmente partecipano in qualsiasi altro studio clinico interventistico;
    • Altro tumore maligno passato o attuale. I soggetti che sono in remissione completa da almeno 5 anni, o hanno una storia di asportazione completa del cancro della pelle di tipo non-melanoma, o soggetti con carcinoma in situ trattato con successo sono eleggibili;
    • Malattia infettiva cronica o corrente che richiede come trattamento l’uso di antibiotici sistemici, antifungini o antivirali, escludendo l'infezione cronica renale, infezioni croniche al torace con bronchiectasie, tubercolosi e l'epatite C attiva;
    • Storia di una significativa malattia cerebrovascolare negli ultimi 6 mesi o degli eventi in corso con sintomi attivi o sequele;
    • Positività HIV;
    • Malattia cardiaca clinicamente significativa, ivi incluso l'angina instabile, infarto miocardico acuto nei sei mesi precedenti l'inizio del trattamento, insufficienza cardiaca congestizia (NYHA III-IV), e aritmia non controllata da terapia, con l'eccezione di extrasistole o anomalie minori di conduzione;
    • Significativa concomitante condizione clinica incontrollata, comprese, ma non limitato a, renale, epatica, gastrointestinale, endocrina, malattia polmonare, neurologica, cerebrale o psichiatrica che, a parere del ricercatore potrebbe rappresentare un rischio per il paziente;
    • Sierologia positiva per epatite B (HB) definita come test positivo per HBsAg. Inoltre, se negativa per HBsAg ma positivo per HBcAb (indipendentemente dallo stato HBsAb), verrà eseguito un test per HBV-DNA e se l’esito sarà positivo il soggetto sarà da escludere;
    • Sierologia positiva per epatite C (HC) definita come test positivo per HCAb. Se positivo in aggiunta si deve eseguire un test per HCV-RNA sullo stesso campione per confermare il risultato;
    • Criteri di esclusione ematologici e biochimici :
    o piastrine <50 x 109 / L;
    o neutrofili <1,0 x 109 / L;
    o creatinina> 2,0 volte il limite superiore della norma;
    o bilirubina totale> 1,5 volte il limite superiore della norma;
    o ALT> 2,5 volte il limite superiore della norma;
    o fosfatasi alcalina> 2,5 volte il limite superiore della norma;
    • Donne in gravidanza o allattamento. Le donne in età fertile devono risultare negative al test di gravidanza allo screening. Donne in età fertile, tra cui donne il cui ultimo periodo mestruale è stato inferiore a un anno prima dello screening, incapaci o riluttanti ad usare adeguati metodi contraccettivi dall'inizio studio e per un anno dopo l'ultima dose della terapia prevista dal protocollo. I metodi contraccettivi adeguati sono definiti come il controllo ormonale delle nascite, il dispositivo intrauterino, il metodo a doppia barriera o l’astinenza totale.
    • I soggetti maschi che non possono o non vogliono utilizzare metodi contraccettivi adeguati dall'inizio studio per un anno dopo l'ultima dose di protocollo di terapia.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of Bcl-2 negativization after Ofatumumab treatment will be estimated by the proportion, and its confidence interval, of residual Bcl-2 positive cases after radiotherapy, which will became negative after Ofatumumab treatment.
    Valutazione della percentuale di negativizzazione della Bcl-2 dopo il trattamento con Ofatumumab e il suo intervallo di confidenza nei casi residui Bcl-2 positivi dopo la radioterapia.
    E.5.1.1Timepoint(s) of evaluation of this end point
    30 months
    30 mesi
    E.5.2Secondary end point(s)
    Clinical response rate will be evaluated by the proportion and its confidence interval of patients achieving overall response (OR) complete response (CR) and partial response (PR).

    Progression Free Survival (PFS) is defined as the length of time between the date of treatment conclusion and the earliest date of disease progression or death due to any cause; If the patients doesn’t not have a documented date of progression or death, the PFS will be censored at the date of last adequate assessment. Relapse Free Survival (RFS) is defined as the length of time between the achievement of Complete Remission (CR) and Relapse of disease
    RFS and PFS in patients treated with local radiotherapy and molecularly–based Ofatumumab consolidation and/or retreatment will be evaluated by Kaplan-Meier survival analysis.
    • Risposta clinica: il tasso di risposta clinica sarà valutato in base alla proporzione ed al suo intervallo di confidenza della risposta globale (OR), della risposta completa (CR) e risposta parziale (PR).
    • Sopravvivenza senza progressione (PFS) definita come l'intervallo di tempo tra la data di conclusione del trattamento e la prima data della progressione della malattia o morte per qualsiasi causa; se i pazienti non hanno una data documentata di progressione o morte, il PFS sarà censurato alla data dell'ultima valutazione adeguata. La sopravvivenza libera da recidiva (RFS) è definita come l'intervallo di tempo tra il conseguimento della remissione completa (CR) e la recidiva della malattia.
    • RFS e PFS nei pazienti trattati con radioterapia locale e con Ofatumumab di consolidamento e / o ritrattamento valutate mediante analisi di sopravvivenza Kaplan-Meier.
    E.5.2.1Timepoint(s) of evaluation of this end point
    72 months
    72 mesi
    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 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. 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 No
    E.8.1.2Open Yes
    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 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 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 concerned50
    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 No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state110
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 110
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of participation in the study patients will be followed as
    required by standard practice.
    Al termine della partecipazione allo studio i pazienti verranno seguiti
    secondo quanto previsto dalla comune 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 Decision2014-10-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-09
    P. End of Trial
    P.End of Trial StatusOngoing
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