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    Summary
    EudraCT Number:2012-004023-20
    Sponsor's Protocol Code Number:CLDE225X2116
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-04-09
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2012-004023-20
    A.3Full title of the trial
    A Phase Ib/II, open-label, multi-center, dose-finding study to assess the safety and efficacy of the oral combination of LDE225 and INC424 (Ruxolitinib) in patients with myelofibrosis
    Estudio de fase Ib/II, abierto, multicéntrico, de determinación de dosis para evaluar la seguridad y eficacia de la combinación oral de LDE225 e INC424 (Ruxolitinib) en pacientes con mielofibrosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating the safety and efficacy of LDE225 and INC424 in patients with myelofibrosis
    Estudio de investigación de la seguridad y eficacia de LDE225 y INC424 en pacientes con mielofibrosis
    A.4.1Sponsor's protocol code numberCLDE225X2116
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01787552
    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 Farmacéutica S.A.
    B.1.3.4CountrySpain
    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 Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica S.A.
    B.5.2Functional name of contact pointDepartamento médico Oncología (GMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Via de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code080136
    B.5.3.4CountrySpain
    B.5.4Telephone number+34900353036
    B.5.5Fax number+34932479903
    B.5.6E-maileecc.novartis@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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLDE225
    D.3.4Pharmaceutical form Capsule
    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 INNsonidegib
    D.3.9.1CAS number 1218778-77-8
    D.3.9.2Current sponsor codeLDE225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 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 Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/620, EU/3/08/572
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRuxolitinib
    D.3.9.1CAS number 1092939-17-7
    D.3.9.2Current sponsor codeINC424
    D.3.9.3Other descriptive nameRUXOLITINIB PHOSPHATE
    D.3.9.4EV Substance CodeSUB32897
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    myelofibrosis
    mielofibrosis
    E.1.1.1Medical condition in easily understood language
    A disorder of the bone marrow
    Un trastorno de la médula ósea
    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 PT
    E.1.2Classification code 10028537
    E.1.2Term Myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish the MTD and/or recommended phase II dose of the co-administration of LDE225 and INC424 in patients with MF, who have not previously received therapy with a JAK inhibitor
    Fase Ib: establecer la MTD y/o la RPIID de la combinación de LDE225 (QD) e INC424 (BID) cuando se administran por vía oral a pacientes con MF que no han recibido previamente tratamiento con inhibidores de JAK y Smo.
    Fase II: valorar la eficacia de la administración conjunta de LDE225 e INC424 sobre la reducción del volumen del bazo determinada mediante RM/TC revisada centralmente.
    E.2.2Secondary objectives of the trial
    - To evaluate the safety of the co-administration of LDE225 and INC424 in patients with MF
    - To characterize the single and multiple dose pharmacokinetics following the co-administration of LDE225 and INC424
    Fase Ib:
    Evaluar la seguridad de la administración conjunta de LDE225 e INC424 en pacientes con MF.
    Caracterizar la farmacocinética de dosis únicas y múltiples después de la administración conjunta de LDE225 e INC424.
    Fase II:
    - Valorar el efecto de la administración conjunta de LDE225 e INC424 sobre la fibrosis de la médula ósea mediante revisión central y sobre biomarcadores farmacodinámicos específicos de la enfermedad como función de la caracterización de enfermedad molecular de la MF.
    - Evaluar la seguridad de la administración conjunta de LDE225 e INC424 en pacientes con MF
    - Caracterizar la farmacocinética de dosis únicas y múltiples después de la administración conjunta de LDE225 e INC424
    - Valorar el efecto de la administración conjunta de LDE225 e INC424 sobre los síntomas asociados a la MF
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Diagnosed with PMF per 2008 WHO criteria, post-PV MF or post-ET MF per IWG-MRT criteria.
    - Ineligible or unwilling to undergo stem cell transplantion.
    - PLT counts > or = 75X 10^9/L not reached with the aid of transfusions.
    - ECOG performance status ? 2.
    - Palpable splenomegaly defined as ? 5 cm below the left costal margin.
    - Intermediate risk level 1 (1 prognostic factor which is not age), Intermediate risk level 2, or high risk.
    - Active symptoms of MF.

    Other protocol defined inclusion criteria may apply.
    - El paciente ha de tener un diagnóstico de MF primaria según los criterios de 2008 de la OMS, o MF post-PV o post-ET según los criterios del IWG-MRT
    - El paciente no es elegible o no desea que se le practique trasplante deprogenitores hematopoyéticos
    - El paciente no llega a un recuento de plaquetas ? 75 x 109/l con la ayuda de transfusiones
    - El paciente tiene un estado funcional del Eastern Cooperative Oncology Group (ECOG) ? 2 en la Selección
    - El paciente ha de presentar esplenomegalia palpable definida como ? 5 cm por debajo del borde costal izquierdo
    - El paciente ha de tener un riesgo intermedio de grado 1 (1 factor de pronóstico que no sea la edad), un riesgo intermedio de grado 2, o riesgo alto según los criterios del IWG
    - El paciente ha de tener, en la Selección, síntomas activos de MF demostrados por una puntuación sintomática igual o superior a 5 (escala de 0 a10 puntos) o dos puntuaciones sintomáticas igual o superiores a 3 (escala de 0 a10 puntos) en el formulario de evaluación de los síntomas de mielofibrosis (MFSAF)
    E.4Principal exclusion criteria
    -Previous therapy with JAK or Smoothened inhibitors.
    - Patient is currently on medications that interfere with coagulation (including warfarin) or platelet function with the exception of low dose aspirin (up to 100 mg) and LMWH.
    - Impairment of GI function or GI disease that may significantly alter the absorption of INC424 or LDE225 (e.g., uncontrolled nausea, vomiting, diarrhea; malabsorption syndrome; small bowel resection).
    - Splenic irradiation within 12 months prior to Screening.
    - Pregnant or nursing women.
    - Women of childbearing potential not using highly effective methods of contraception
    - Sexually active males who refuse condom use
    - Patients who have neuromuscular disorders or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis.

    Other protocol defined exclusion criteria may apply.
    - Terapia previa con inhibidores de JAK
    - Terapia previa con un inhibidor de la proteína Smoothened
    - El paciente presenta disfunción cardíaca o cardiopatía clínicamente significativa
    - El paciente está tomando actualmente medicamentos que interfieren con la coagulación (incluida warfarina) o con la función plaquetaria con la excepción del ácido acetilsalicílico a dosis baja (hasta 100 mg) y LMWH
    - El paciente tiene un trastorno de la función gastrointestinal (GI) o enfermedad GI que puede alterar significativamente la absorción de INC424 o LDE225 (p. ej., náuseas incontroladas, vómitos, diarrea; síndrome de malabsorción; resección de intestino delgado)
    - Al paciente se le haya realizado radioterapia esplénica en el plazo de 12 meses antes de la Selección
    - Pacientes que padecen trastornos neuromusculares (p.ej. miopatías inflamatorias, distrofia muscular, esclerosis lateral amiotrófica y atrofia de la musculatura vertebral) o están en tratamiento concomitante con fármacos que se sabe que causan rabdomiólisis, como inhibidores de la HMG CoA (estatinas), clofibrato y gemfibrozil. La pravastatina se puede utilizar si es necesario, extremando la precaución
    - Pacientes que tienen previsto empezar nuevas (o no habitualess) actividades físicas, como ejercicio extenuante, que puede dar lugar a aumentos significativos de la concentración sanguínea de CK durante el tratamiento del estudio. NOTA: Como precaución, se evitará toda actividad muscular extenuante durante por lo menos 1 semana antes de la determinación de la concentración sanguínea de CK
    - Pacientes que reciban tratamiento con medicamentos que se sabe que son inhibidores o inductores moderados y potentes de CYP3A4/5 o fármacos que se metabolizan por CYP2B6 o CYP2C9 que tienen un índice terapéutico estrecho, y que no se puedan suspender antes de iniciar el tratamiento con LDE225. Los medicamentos que son inhibidores potentes de CYP3A4/5 se han de suspender por lo menos 7 días y los inductores potentes de CYP3A/5 por lo menos 2 semanas antes del inicio del tratamiento con LDE225
    E.5 End points
    E.5.1Primary end point(s)
    Dose Limiting Toxicities (DLTs) occurring during the first 6 weeks of the co-administration of INC424 and LDE225
    Se producen toxicidades limitantes de dosis (DLTs) durante las 6 primeras semanas de la administración conjunta de INC424 e LDE225
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the first 6 weeks of the co-administration of INC424 and LDE225
    Durante las primeras 6 semanas de la co-administración de INC424 y LDE225
    E.5.2Secondary end point(s)
    - Adverse and serious adverse events, abnormalities in physical examinations, vital signs and laboratory test values, including ECG data
    - LDE225 and INC424 PK parameters
    - Acontecimientos adversos y acontecimientos adversos graves, anomalías en la exploraciones físicas, constantes vitales y valores de las pruebas de laboratorio, incluidos datos del ECG
    - Parámetros PK de LDE225 e INC424
    E.5.2.1Timepoint(s) of evaluation of this end point
    As defined in Table 7-1 of the protocol.
    Tal como se define en la Tabla 7-1 del protocolo.
    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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    dose finding study
    estudio de búsqueda de dosis
    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 No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    Denmark
    France
    Germany
    Ireland
    Italy
    Netherlands
    Russian Federation
    Spain
    United Kingdom
    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
    LVLS
    El estudio finalizará cuando el último paciente complete 2 años de tratamiento o 30 días después de que el último paciente sea retirado del estudio, o cuando el estudio finalice de forma prematura, lo que ocurra primero.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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: 41
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 41
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 65
    F.4.2.2In the whole clinical trial 82
    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)
    none (expected normal treatment of that condition).
    ninguno (tratamiento normal esperado de esa condición).
    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 Decision2013-06-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-04-10
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