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    Summary
    EudraCT Number:2009-010982-22
    Sponsor's Protocol Code Number:DSC/08/2357/38
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-05-13
    Trial results View 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 number2009-010982-22
    A.3Full title of the trial
    Phase II study of the histone-deacetylase inhibitor GIVINOSTAT (ITF2357) in combination with hydroxyurea in patients with JAK2V617F positive Polycythemia Vera non-responder to hydroxyurea monotherapy
    Studio di fase II con l inibitore dell istone deacetilasi GIVINOSTAT (ITF2357) in associazione con Idrossiurea in pazienti affetti da Policitemia Vera JAK2V617F positivi, che non hanno risposto al trattamento in monoterapia con Idrossiurea
    A.3.2Name or abbreviated title of the trial where available
    GIVINOSTAT + Hydroxyurea in Polycythemia Vera
    GIVINOSTAT + Idrossiurea in Policitemia Vera
    A.4.1Sponsor's protocol code numberDSC/08/2357/38
    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 SponsorITALFARMACO
    B.1.3.4CountryItaly
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameGIVINOSTAT
    D.3.2Product code ITF2357
    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 INNC1-inhibitor
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number50
    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 Yes
    D.3.11.13.1Other medicinal product typeinibitore degli istoni deacetilasi (HDAC)
    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
    Polycythemia Vera
    Policitemia Vera
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLT
    E.1.2Classification code 10018847
    E.1.2Term Haematological disorders
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of GIVINOSTAT (ITF2357) in combination with hydroxyurea in patients with JAK2V617F positive Polycythemia Vera non-responders to the maximum tolerated dose of hydroxyurea monotherapy
    Valutare l efficacia di GIVINOSTAT (ITF2357) in associazione con Idrossiurea in pazienti affetti da Policitemia Vera JAK2V617F positivi, che non hanno risposto al trattamento con la massima dose tollerata di Idrossiurea in monoterapia
    E.2.2Secondary objectives of the trial
    - To evaluate the safety and tolerability of GIVINOSTAT (ITF2357) in combination with hydroxyurea in patients with JAK2V617F positive Polycythemia Vera non-responders to the maximum tolerated dose of hydroxyurea monotherapy. - To explore the impact in terms of efficacy and tolerability of GIVINOSTAT (ITF2357) 50 mg dose escalation in patients not achieving at least a partial response at the time when the primary endpoint is assessed (week 12). - To evaluate the molecular response (JAK2 mutated allele burden) by quantitative RT-PCR. - To evaluate the reduction of the fraction of JAK2V617F positive clonogenic progenitors.
    - Valutare la sicurezza e la tollerabilita` del trattamento con GIVINOSTAT (ITF2357) in combinazione con Idrossiurea in pazienti affetti da Policitemia Vera JAK2V617F positivi che hanno avuto una risposta meno che parziale (ovvero che non hanno risposto) al trattamento con la massima dose tollerata di Idrossiurea in monoterapia.- Esplorare l impatto in termini di efficacia e di tollerabilita` di un aumento di 50 mg della dose di GIVINOSTAT (ITF2357) nei pazienti che non hanno raggiunto almeno una risposta parziale dopo 12 settimane di trattamento combinato con Idrossiurea.- Valutare la risposta molecolare della mutazione V617F del gene JAK2 mediante RT-PCR quantitativa.- Valutare la riduzione della quota dei progenitori clonogenici JAK2V617F positivi rispetto a quelli negativi.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Written Informed Consent. Age &#8805;18 years. Confirmed diagnosis of Polycythemia Vera according to the revised WHO criteria. JAK2V617F positivity. Non-response to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months. ECOG performance status <3. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential. Willingness and capability to comply with the requirements of the study.
    consenso informato firmato dal paziente; maschio o femmina, di eta` &gt; 18 anni; diagnosi confermata di Policitemia Vera secondo i criteri WHO; positivita` alla mutazione JAK2V617F; esposizione pregressa per almeno 3 mesi alla monoterapia con Idrossiurea alla massima dose tollerata senza raggiungimento di alcuna risposta ematologica; ECOG performance status &lt; 3; utilizzo di un metodo anticoncezionale efficace per le donne in eta` fertile e gli uomini con partners in eta` fertile; disponibilita` e capacita` di seguire le procedure richieste dallo studio.
    E.4Principal exclusion criteria
    Active bacterial or mycotic infection requiring antimicrobial treatment. Pregnancy or lactation. A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett s correction formula). Use of concomitant medications that prolong the QT/QTc interval. Clinically significant cardiovascular disease including: - Uncontrolled hypertension, myocardial infarction, unstable angina within 6 months from study start; - New York Heart Association (NYHA) Grade II or greater congestive heart failure; - History of any cardiac arrhythmia requiring medication (irrespective of its severity); - A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome). Positive blood test for HIV. Active HBV and/or HCV infection. Platelets count <100x109/L within 14 days before enrolment. Absolute neutrophil count <1.2x109/L within 14 days before enrolment. Serum creatinine >2xULN. Total serum bilirubin >1.5xULN. Serum AST/ALT > 3xULN. History of other diseases, metabolic dysfunctions, physical examination findings, or clinical laboratory findings giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications. Interferon alpha within 14 days before enrolment. Anagrelide within 7 days before enrolment. Any other investigational drug within 28 days before enrolment.
    infezioni attive batteriche o micotiche che richiedono il trattamento con antimicrobici; gravidanza o allattamento; marcato prolungamento dell intervallo QT/QTc (per esempio una dimostrazione ripetuta di QTc &gt; 450 msec, calcolato secondo la formula di Bazett); uso di farmaci concomitanti che potrebbero prolungare l intervallo del QT/QTc; patologie cardiovascolari clinicamente rilevanti, quali: 1. ipertensione non controllata, infarto del miocardio, angina instabile nei 6 mesi precedenti l`inizio dello studio; 2. scompenso cardiaco di grado 2 o superiore, secondo i criteri NYHA (New York Heart Association); 3. storia di un qualsiasi tipo di aritmia cardiaca che ha richiesto un trattamento (indipendentemente dalla sua severita`); 4. presenza di fattori di rischio per torsione di punta (per esempio infarto, ipocaliemia, storia familiare di sindrome del QTc lungo); infezione da HIV; infezione da epatite B e/o C attiva; PLT &lt;100x109/L entro 14 giorni dall arruolamento; ANC &lt;1.2x109/L entro 14 giorni dall arruolamento; Creatinina sierica &gt;2xULN; Bilirubina sierica totale &gt;1.5xULN; AST/ALT sieriche &gt; 3xULN; storia di altre patologie, disfunzioni metaboliche, riscontri obiettivi, reperti clinici o laboratoristici che inducano al sospetto di una condizione che possa rappresentare una controindicazione all uso di un farmaco sperimentale, inficiare l interpretazione dei dati o esporre il paziente ad elevato rischio di complicanze; trattamento con Interferone nei 14 giorni precedenti l arruolamento; trattamento con Anagrelide nei 7 giorni precedenti l arruolamento; qualsiasi altro farmaco sperimentale nei 28 giorni precedenti l arruolamento.
    E.5 End points
    E.5.1Primary end point(s)
    Overall response rate (partial and complete responses) at week 12.
    Numero di risposte (risposte parziali + complete) al trattamento dopo 12 settimane di terapia combinata GIVINOSTAT (ITF2357) - Idrossiurea
    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 Yes
    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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    - Stesso farmaco ad altro dosaggio
    - same IMP used at different dosage
    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 concerned20
    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 years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    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.1.3Elderly (>=65 years) Yes
    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 state44
    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)
    Dopo aver completato lo studio, i pazienti che hanno ricevuto un beneficio terapeutico potranno continuare ad assumere GIVINOSTAT (ITF2357) secondo uso compassionevole, in accordo col parere medico dello Sperimentatore.
    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 Decision2009-04-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-04-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-07-07
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