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    Summary
    EudraCT Number:2006-006852-37
    Sponsor's Protocol Code Number:CPKC412A2301
    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:2008-10-23
    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 number2006-006852-37
    A.3Full title of the trial
    A phase III randomized, double-blind study of induction(daunorubicin/cytarabine)and consolidation (high dose cytarabine) chemotherapy + midostaurin (PKC412)(IND-101261) or placebo in newly diagnosed patients < 60 years of age with FLT3 mutated acute myeloid laukemia (AML)
    Studio randomizzato di fase III, in doppio cieco, per valutare la chemioterapia di induzione (daunorubicina/citarabina) e di consolidamento (citarabina a dosi elevate) in associazione a midostaurina (PKC412) (IND-101261) o placebo in pazienti di eta' inferiore a 60 anni con leucemia mieloide acuta (AML) di nuova diagnosi.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ND
    ND
    A.4.1Sponsor's protocol code numberCPKC412A2301
    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 SponsorNOVARTIS FARMA
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNOVARTIS FARMA
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityORIGGIO
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number+39 02 96541
    B.5.5Fax number+39 02 9659066
    B.5.6E-mailinfo.studiclinici@novartis.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/04/214
    D.3 Description of the IMP
    D.3.1Product nameMidostaurina
    D.3.2Product code PKC412
    D.3.4Pharmaceutical form Capsule, soft
    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 INNMidostaurin
    D.3.9.1CAS number 120685-11-2
    D.3.9.2Current sponsor codePKC412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number25
    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: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country 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.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCytarabine
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.3Concentration number100
    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: 3
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country 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.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDaunorubicin
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number20
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    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
    acute myeloid leukemia
    leucemia mieloide acuta (AML) di nuova diagnosi
    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 LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if the addition of midostaurin to daunorubicin/cytarabine induction, high dose cytarabine consolidation and continuation therapy improves overall survival in both the mutant FLT3-ITD and FLT3-TKD AML patinets
    Stabilire se l`aggiunta di midostaurina alla terapia di induzione con daunorubicina/citarabina, alla terapia di consolidamento con dosi elevate di citarabina e alla terapia continuativa, migliora la sopravvivenza globale (OS) nei pazienti con leucemia mieloide acuta con mutazione FLT3-ITD e con mutazione FLT3-TKD.
    E.2.2Secondary objectives of the trial
    1.To compare the overall survival (OS) in the two groups using an analysis in which patient who receive a stem cell transplant are censored at the time of transplant. 2.To compare the CR rate between the two treatment groups. 3.To compare the event-free survival(EFS) between the two treatment groups. 4.To compare the DFS of the two treatment groups. 5.To compare the DFS rate one year after completion of the continuation phase of the two groups. 6.To assess the toxicity of the experimental combination. 7.To describe the interaction between treatment outcome and pretreatment characteristics such as age, performance status, white blood cell (WBC) count,morphology, cytogenetics, and molecular and pharmacodynamic features. 8.To assess the population pharmacokinetics(popPK) of midostaurin and its two major metabolites, CGP52421 and CGP62221. The potential association(s)between PK exposure and FLT3 status, OS, EFS and clinical response will will be explored.
    1.Confr.la sopravvivenza globale(OS)nei due gruppi utilizzando un`analisi per cui paz sottoposti a trapianto sono censorizzati al momento del trapianto.2.Confr.la frequenza di CR tra i due gruppi di tratt.3.Confr.la sopravvivenza libera da eventi(EFS)tra i due gruppi di tratt.4.Confr.la sopravvivenza libera da malattia(DFS)tra i due gruppi di tratt.5.Confr.la frequenza di sopravvivenza libera da malattia(DFS)un anno dopo il completamento della fase continuativa tra i due gruppi di tratt.6.Valut la tossicità dell`associazione in studio.7.Descrivere l`interazione tra l`esito del tratt e le caratteristiche pre-tratt quali età,performance status,conta leucocitaria(WBC),morfologia,citogenetica e caratteristiche molecolari e farmacodinamiche.8.Valut la farmacocinetica di pop della midostaurina e dei suoi due metabolici,CGP52421 e CGP62221.Saranno esplorate la/e potenziale/i associazione/i tra esposizione e status FLT3,sopravvivenza globale,sopravvivenza libera da eventi e risp clinica.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Unequivocal diagnosis of AML (>20% blasts in the bone marrow based on the WHO classification), excluding M3 (acute promyelocytic leukemia. Patients with neurologic symptoms suggestive of CNS leukemia are recommended to have a lumbar puncture. Patients whose CSF is positive for AML blasts are not elegible - Documented FLT3 mutation - Age >18 and < 60 years - No prior chemotherapy for leukemia or myelodysplasia with few exception listed (see protocol page 7) - AML patients with a history of antecedent myelodysplasia (MDS) remain eligible for treatment on this trial, but must not have had prior cytotoxic therapy (e.g., azacitidine or decitabine). `€' Total bilirubin < 2.5 upper limit of normal
    1.Diagnosi inequivocabile di leucemia mieloide acuta (&gt; 20% blasti nel midollo osseo in base alla classificazione WHO), escludendo M3 (leucemia promielocitica acuta). Si raccomanda l`esecuzione di una rachicentesi nei pazienti con sintomi neurologici indicativi di leucemia. I pazienti con presenza di blasti di leucemia mieloide acuta nel liquido cefalorachidiano non sono eleggibili. 2.Mutazione FLT3 documentata (ITD o mutazione puntiforme) determinata mediante analisi di laboratorio di screening FLT3 (vedi sezione 6.0 del protocollo). 3.Eta` uguale o superiore a 18 anni e &lt; 60 anni. 4.Nessuna chemioterapia precedente per leucemia o mielodisplasia con le seguenti eccezioni: leucaferesi d`emergenza, trattamento d`emergenza per iperleucocitosi con idrossiurea per `‰¤ 5 giorni, radioterapia cranica per leucostasi del sistema nervoso centrale (una sola dose), supporto con fattore di crescita/citochina. 5.I pazienti con anamnesi positiva per mielodisplasia sono eleggibili allo studio ammesso che non siano stati sottoposti a precedente terapia citotossica (ad es: azacitizina o decitabina). 6.Bilirubina totale &lt; 2.5 x ULN.
    E.4Principal exclusion criteria
    - Patients who have developed therapy related AML after prior RT or chemotherapy for another disorder or cancer - Patients with symptomatic congestive heart failure - Non pregnant and non-nursing
    I pazienti che hanno manifestato una leucemia mieloide acuta correlata al trattamento dopo precedente radioterapia o chemioterapia per un`altra neoplasia o un`altra patologia non sono eleggibili allo studio. • I pazienti con insufficienza cardiaca congestizia non sono eleggibili allo studio. • Donne in gravidanza o durante l`allattamento. Il potenziale teratogeno di midostaurina non e` noto;pertanto, le donne in gravidanza o in allattamento non possono essere arruolate. Le donne che possono concepire devono avere un test di gravidanza negativo sul siero o sulle urine con una sensibilita` di almeno 50 mIU/mL entro 16 giorni dalla registrazione nello studio. Le donne che possono concepire devono impegnarsi a praticare astinenza completa dai rapporti eterosessuali durante lo studio o impegnarsi a praticare DUE metodi contraccettivi accettabili: un metodo altamente efficace (ad es: IUD, contraccezione ormonale (contraccezione non orale), legatura delle tube o vasectomia del partner) e un metodo efficace aggiuntivo (ad es: preservativo di lattice,diaframma o cappuccio cervicale) IN CONCOMITANZA, prima dell`inizio della terapia con midostaurina/placebo e per 12 settimane dopo la somministrazione dell`ultima dose di midostaurina. E` importante notare che i contraccettivi orali non sono considerati un metodo altamente efficace per la possibilita` di interazione farmacologica con midostaurina. Le donne potenzialmente fertili sono definite donne sessualmente mature e attive che non sono state sottoposte a isterectomia o che hanno avuto mestruazioni consecutivamente nei 24 mesi precedenti. I pazienti di sesso maschile devono acconsentire a non provocare una gravidanza nella partner e a utilizzare un preservativo di lattice durante ogni rapporto sessuale con donne che possono concepire durante l`assunzione di midostaurina/placebo e per 12 settimane dopo il termine della terapia, anche se sottoposti a vasectomia efficace.Le seguenti condizioni possono aumentare il rischio per la sicurezza del paziente: • Altre patologie gravi che limitano la sopravivenza a &lt; 2 anni o patologie psichiatriche che compromettono l`aderenza del paziente al trattamento o la capacita` di fornire il proprio consenso informato allo studio. • Angina pectoris grave o non controllata, diabete, infezione o pneumopatia che, nell`opinione dello sperimentatore, rendano rischiosa la partecipazione del paziente allo studio. • Pazienti con un`altra neoplasia (diversa dal basalioma cutaneo) `€œattualmente in fase attiva'. • La midostaurina e` un inibitore competitivo di CYP3A4/5. Alcuni studi mostrano che il CYP3A4 e` il principale enzima del sistema p450 che catalizza la biotrasformazione della midostaurina. La somministrazione concomitante di farmaci forti induttori (ad es difenilidantoina) o, soprattutto, forti inibitori (ad es itraconazolo) di questi enzimi puo` diminuire o aumentare le concentrazioni di midostaurina e diminuirne l`efficacia nel primo caso o aumentarne la tossicita` nel secondo caso(nell`Appendice I e` riportato l`elenco dei farmaci che possono determinare interazioni farmacologiche).
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival (OS)
    La variabile di efficacia primaria e` la sopravvivenza globale (OS) nei pazienti con leucemia mieloide acuta con mutazione FLT3-ITD e nei pazienti con leucemia mieloide acuta con mutazione FLT3-TKD. Il tempo alla sopravvivenza globale e` l`intervallo di tempo che intercorre tra la data di registrazione nello studio e il decesso da qualsiasi causa
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) 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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    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 concerned25
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA124
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months66
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months66
    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.1.1Number 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) No
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 260
    F.4.2.2In the whole clinical trial 714
    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 Decision2008-10-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-09-17
    P. End of Trial
    P.End of Trial StatusCompleted
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