Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   41200   clinical trials with a EudraCT protocol, of which   6743   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).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2018-000588-99
    Sponsor's Protocol Code Number:BLU-285-2203
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-16
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2018-000588-99
    A.3Full title of the trial
    A 3-Part, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate Safety and Efficacy of Avapritinib (BLU-285), a Selective KIT Mutation-Targeted Tyrosine Kinase Inhibitor, in Indolent and Smoldering Systemic Mastocytosis with Symptoms Inadequately Controlled with Standard Therapy
    Estudio en fase II, aleatorizado, doble ciego, controlado con placebo, de 3 partes para evaluar la seguridad y eficacia de avapritinib (BLU 285), un inhibidor selectivo de la tirosina cinasa dirigido a mutaciones en KIT, en la mastocitosis sistémica indolente y latente con control insuficiente de los síntomas con el tratamiento de referencia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Avapritinib in Patients with Indolent and Smoldering Systemic Mastocytosis
    Un estudio de avapritinib en pacientes con mastocitosis sistémica indolente y latente
    A.3.2Name or abbreviated title of the trial where available
    Pioneer
    A.4.1Sponsor's protocol code numberBLU-285-2203
    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 SponsorBlueprint Medicines Corporation
    B.1.3.4CountryUnited States
    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 supportBlueprint Medicines Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationINC Research
    B.5.2Functional name of contact pointProject Director, Global Oncology
    B.5.3 Address:
    B.5.3.1Street Address3201 Beechleaf Ct, Suite 600
    B.5.3.2Town/ cityRaleigh
    B.5.3.3Post codeNC 27604
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1512904 4317
    B.5.6E-mailsara.hoffman@syneoshealth.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 nameAvapritinib
    D.3.2Product code BLU-285, C-366, C366, 70C366, X720776, BLU112317
    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 INNAvapritinib
    D.3.9.2Current sponsor codeBLU-285
    D.3.9.4EV Substance CodeSUB178877
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    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 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 nameAvapritinib
    D.3.2Product code BLU-285, C-366, C366, 70C366, X720776, BLU112317
    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 INNAvapritinib
    D.3.9.2Current sponsor codeBLU-285
    D.3.9.4EV Substance CodeSUB178877
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Indolent and Smoldering Systemic Mastocytosis (ISM & SSM)
    Mastocitosis sistémica indolente y latente ( MSI y MSL)
    E.1.1.1Medical condition in easily understood language
    Mastocytosis
    Mastocitosis
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10042949
    E.1.2Term Systemic mastocytosis
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10056452
    E.1.2Term Indolent systemic mastocytosis
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1 - to determine the RP2D in patients with ISM for use in Part 2 and Part 3 of the study.
    Part 2 - to determine the effect of avapritinib in reducing symptoms in ISM and SSM patients, as compared to placebo.
    Part 3 - to assess the long-term safety and efficacy of avapritinib in ISM and SSM patients.
    Parte 1- determinar la DRF2 en pacientes con MSI para su uso en la Parte 2 y la Parte 3 del estudio.
    Parte 2- determinar el efecto de avapritinib en la reducción de los síntomas en pacientes con MSI y MSL, en comparación con el placebo.
    Parte 3- evaluar la seguridad y la eficacia a largo plazo de avapritinib en pacientes con MSI y MSL.
    E.2.2Secondary objectives of the trial
    Part 1 and Part 2, assess:
    Change in measures of MC burden, cutaneous disease and BSC usage; Change from baseline to wk 12 for ISM-SAF "lead symptom" score, proportion of patients with and time to achieve 5, 10 and 15-pt reductions in TSS and domain scores, and change in individual symptom scores; Change in other PROs based on the MC-QoL, PGIS, SF-12, PGIC and the EQ 5D-5L questionnaires; Change in the frequency of anaphylactic episodes; Safety and tolerability of avapritinib, as assessed by AEs, vital signs, ECGs and lab tests; PK of avapritinib; Correlate exposure with safety and efficacy endpoints

    Part 3, assess:
    Change in the measures of MC burden, cutaneous disease and BSC usage; Change in ISM-SAF "lead symptom" score, TSS, domain scores and individual symptom from Part 3 baseline to wk 12, 24, 36 and 52; Time to achieve those reductions; Change in other PROs; Change in the frequency of anaphylactic episodes; Safety and tolerability of avapritinib.
    Parte 1 y 2:cambio en medidas de carga de MC,enf. cutánea y uso de med. concom.;cambio en puntuación de “síntoma principal” de ISM-SAF desde inicio hasta sem. 12;proporción de pacientes con reducciones de 5,10 y 15 puntos y tiempo hasta conseguirlas en TSS y en punt. de dominios desde inicio hasta sem.12,y cambio en punt. de síntomas individuales;cambio en otros RNPs basados en MC-QoL,PGIS,SF-12,PGIC y EQ 5D-5L;cambio en frecuencia de ep. anafilácticos;seguridad y tolerabilidad de avapritinib,evaluadas por AAs,CVs,ECGs y analíticas;FC de avapritinib;correlacionar exposición a avapritinib con valoraciones de seguridad y eficacia. Parte 3:cambio en medidas de carga de MC,enf. cutánea y uso de med.concom.;cambio en punt. de “síntoma principal” de ISM-SAF,TSS,punt. de dominios y punt. de síntomas individuales desde inicio de Parte 3 hasta sem. 12,24,36 y 52;tiempo hasta reducciones;cambio en otros RNPs;cambio en frecuencia de ep. anafilácticos;seguridad y tolerabilidad de avapritinib.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients who are at least 18 years of age.
    2. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and ISM or SSM subtype, as confirmed by WHO diagnostic criteria. In Part 1 of the study, only patients with a diagnosis of ISM are eligible.
    3. Patient must have moderate-to-severe symptoms based on minimum mean TSS over the 14-day eligibility screening period for assessment of TSS and at least 1 symptom in skin or GI domains of the ISM-SAF at Baseline. Minimum TSS for eligibility is greater than or equal to 28.
    4. Patient must have failed to achieve symptom control for 1 or more Baseline symptoms measured by ISM-SAF, as determined by the Investigator, with at least 2 of the following symptomatic therapies administered at optimal (approved) dose and for a minimum of 28 days before starting the ISM-SAF for determination of eligibility: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
    5. Patient must have symptom management optimized with symptomatic therapies (eg, H1 and H2 blockers) and the dose must be stable for at least 14 days before starting the ISM-SAF for determination of eligibility.
    6. If the patient is receiving corticosteroids, the dose must be less than or equal to 20 mg/d prednisone or equivalent, and the dose must be stable for at least 14 days before starting the ISM-SAF for determination of eligibility.
    7. Patient must have an Eastern Cooperative Oncology Group Performance Status of 0 to 2.
    8. Patient must give written informed consent.
    1.Pacientes de como mínimo 18 años de edad.
    2.El paciente debe tener MS, confirmada por la revisión anatomopatológica central de la biopsia de MO, y subtipo MSI o MSL, confirmado según los criterios diagnósticos de la OMS. En la Parte 1 del estudio, solo son aptos los pacientes con diagnóstico de MSI.
    3.El paciente debe tener síntomas de moderados a graves en función de la TSS media mínima en el periodo de selección de la aptitud de 14 días para la evaluación de la TSS y al menos 1 síntoma en los dominios cutáneo o GI del ISM-SAF al inicio. La TSS mínima para la aptitud es mayor o igual a 28.
    4.El paciente debe no haber logrado el control de los síntomas en 1 o más síntomas iniciales medidos por el ISM-SAF, según la determinación del investigador, con la administración de al menos 2 de los siguientes tratamientos sintomáticos en una dosis óptima (aprobada) y durante un mínimo de 28 días antes de empezar el ISM-SAF para la determinación de la aptitud: antagonistas de H1, antagonistas de H2, inhibidores de la bomba de protones, inhibidores de leucotrieno, cromolina sódica, corticoesteroides u omalizumab.
    5.El paciente debe tener un tratamiento optimizado de los síntomas con tratamientos sintomáticos (p. ej., antagonistas de H1 y H2) y la dosis debe haber sido estable durante al menos 14 días antes de empezar el ISM-SAF para la determinación de la aptitud.
    6.Si el paciente está recibiendo corticoesteroides, la dosis debe ser menor o igual a 20 mg/día de prednisona o equivalente y haber sido estable durante al menos 14 días antes de iniciar el ISM-SAF para la determinación de la aptitud.
    7.El paciente debe tener un estado general de 0 a 2 según la escala del Grupo de Oncología Cooperativo del Este.
    8.El paciente debe conceder el consentimiento informado por escrito.
    E.4Principal exclusion criteria
    1. Has been diagnosed with any of the following WHO SM subclassifications: CM only, SM-AHN, ASM, MCL, MC sarcoma.
    2. Has been diagnosed with another myeloproliferative disorder.
    3. Has any of the following organ damage C-findings attributable to SM: Cytopenia, Hepatomegaly with ascites and impaired liver function, Palpable splenomegaly with hypersplenism, Malabsorption with hypoalbuminemia and significant weight loss, Skeletal lesions: large osteolytic lesions with pathologic fractures, Life-threatening organ damage in other organ systems that is caused by MC infiltration in tissues.
    4. Meets any of the following laboratory criteria: Aspartate aminotransferase or alanine aminotransferase > 3.0 × ULN, Total bilirubin > 1.5 × ULN; > 3.0 × ULN if due to Gilbert's disease, Albumin < 1 × LLN, eGFR < 30 mL/min/1.73 m^2 or creatinine clearance calculated by Cockcroft-Gault equation < 40 mL/min, Absolute neutrophil count < 1.5 × 10^9/L, Hemoglobin < 10 g/dL, Platelet count < 100 × 10^9/L.
    5. Has received any of the following medications, therapies, or procedures in the timeframes listed: Any prior treatment with avapritinib, Any TKI, including but not limited to masitinib and midostaurin, or investigational agent < 14 days before starting the ISM-SAF for determination of eligibility, Any antineoplastic drug therapy < 28 days before starting the ISM-SAF for determination of eligibility, Radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before starting the ISM-SAF for determination of eligibility, Any hematopoietic growth factor < 14 days before starting the ISM-SAF for determination of eligibility, Any major surgical procedure < 14 days before starting the ISM-SAF for determination of eligibility.
    6. Requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of cytochrome P450 3A4 (CYP3A4).
    7. Has a history of a malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug. The following are exempt from the 3-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
    8. Has a QTcF > 450 msec.
    9. Has a history of a seizure disorder (eg, epilepsy) or requires antiseizure medication.
    10. Has a history of a cerebrovascular accident or transient ischemic attacks within 12 months before the first dose of study drug.
    11. Has a known risk or recent history (12 months before the first dose of study drug) of intracranial bleeding (eg, brain aneurysm).
    12. Has a primary brain malignancy or metastases to the brain.
    13. Has clinically significant, uncontrolled cardiovascular disease, including Grade III or IV congestive heart failure according to NYHA; myocardial infarction or unstable angina within the previous 6 months; clinically significant, uncontrolled arrhythmias, or uncontrolled hypertension.
    14. Is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures, including mandatory BM and skin biopsies, and study restrictions.
    15. Female patients who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 30 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 90 days after the last dose of study drug.
    16. Pregnant women, as documented by a beta-hCG pregnancy test consistent with pregnancy obtained within 7 days before the first dose of study drug. Women with beta-hCG values that are within the range for pregnancy but are not pregnant (false-positives) may be enrolled with written approval of the Sponsor after pregnancy has been excluded. Women of nonchildbearing potential (postmenopausal, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) do not require a serum beta-hCG pregnancy test.
    17. Women who are breast feeding.
    18. Has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the patient, alter the absorption, distribution, metabolism or excretion of the study drug, or impair the assessment of study results.
    19. Is illiterate or otherwise unable or unwilling to complete daily ISM-SAF assessments in the eDiary. Patient must be fluent in the language(s) available for the ISM-SAF and other QoL questionnaires.
    1.Diagnosticado alguna de estas subclasificaciones de MS según OMS: MC solo,MS-NHA,MSA,LMC,Sarcoma de MCs.
    2.Diagnosticado con otro trastorno mieloproliferativo.
    3.Diagnosticado alguno de estos hallazgos C de daño orgánico atribuible a MS:Citopenia,Hepatomegalia con ascitis y función hepática disminuida,Esplenomegalia palpable con hiperesplenismo,Malabsorción con hipoalbuminemia y pérdida de peso significativa,Lesiones óseas: lesiones osteolíticas considerables con facturas patológicas,Daño orgánico con peligro para la vida en otros sistemas orgánicos causado por infiltración de mastocitos en tejidos.
    4.Cumple con alguno de estos criterios analíticos:Aspartato-aminotransferasa o alanina-aminotransferasa >3,0 veces LSN;Bilirrubina total >1,5 veces el LSN; >3,0 veces el LSN si se debe a la enfermedad de Gilbert; Albúmina <1 veces el LIN;IFGe<30 ml/min/1,73 m2 o aclaramiento de creatinina calculado mediante Cockcroft-Gault <40 ml/min;Recuento absoluto de neutrófilos <1,5 x 109/l;Hemoglobina <10 g/dl;Recuento de plaquetas <100 × 109/l;
    5.Recibido cualquiera de siguientes medicamentos, tratamientos o procedimientos en marcos temporales enumerados:Cualquier tratamiento previo con avapritinib;Cualquier TIKs incluidos, entre otros, masitinib y midostaurina, o producto en investigación <14 días antes de empezar ISM-SAF para determinar elegibilidad;Cualquier tratamiento con fármaco antineoplásico <28 días antes de inicio de ISM-SAF;Radioterapia o tratamiento con psoraleno y radiación ultravioleta A (PUVA) <14 días antes de empezar ISM-SAF;Cualquier factor de crecimiento hematopoyético <14 días antes de inicio del ISM-SAF;Cualquier cirugía mayor <14 días antes de inicio de ISM-SAF.
    6.Necesita tratamiento con medicación concomitante que sea inhibidor potente, o inductor potente o moderado del citocromo P450 3A4 (CYP3A4).
    7.Tiene antecedentes de neoplasia maligna que se ha diagnosticado o tratado en 3 años anteriores a primera dosis de fármaco de estudio. Están exentos de límite de 3 años: carcinoma basocelular o espinocelular completamente resecado, cáncer de próstata localizado tratado con intención curativa y carcinoma in situ completamente resecado en cualquier ubicación.
    8.Tiene un QTcF >450 ms.
    9.Tiene antecedentes de trastorno convulsivo (p. ej., epilepsia) o necesidad de medicamentos anticonvulsivos.
    10.Tiene antecedentes de accidente cerebrovascular o de accidentes isquémicos transitorios en 12 meses previos a primera dosis de fármaco de estudio.
    11.Tiene riesgo conocido o antecedentes recientes (en 12 meses previos a primera dosis de fármaco de estudio) de hemorragia intracraneal (p. ej., aneurisma cerebral).
    12.Neoplasia maligna cerebral primaria o metástasis cerebrales.
    13.Enfermedad cardiovascular clínicamente significativa y no controlada, como insuficiencia cardíaca congestiva de grado III o IV según NYHA; infarto de miocardio o angina inestable en últimos 6 meses; arritmias no controladas clínicamente significativas; o hipertensión no controlada.
    14.No desea o no puede cumplir con visitas programadas, plan de administración de fármaco, análisis clínicos u otros procedimientos, como biopsias de MO y de piel obligatorias, y restricciones de estudio.
    15.Mujeres que,sin ser posmenopáusicas ni quirúrgicamente estériles, no desean abstenerse de mantener relaciones sexuales o emplear métodos anticonceptivos muy efectivos durante período de administración de fármaco de estudio y durante mínimo de 30 días después de última dosis de fármaco de estudio. Hombres que, sin ser quirúrgicamente estériles, no desean abstenerse de mantener relaciones sexuales o emplear métodos anticonceptivos muy efectivos durante período de administración de fármaco de estudio y durante un mínimo de 90 días después de última dosis de fármaco de estudio.
    16.Mujeres embarazadas, documentado por una prueba de embarazo de beta-hCG en suero indicativa de embarazo, realizada en 7 días previos a primera dosis de fármaco de estudio.Mujeres con valores de beta-hCG dentro de intervalo de embarazo pero no embarazadas (falsos positivos) pueden inscribirse con autorización por escrito de promotor, una vez descartado embarazo. No es necesario hacer prueba de embarazo de beta-hCG en suero a mujeres sin capacidad de concebir (posmenopáusicas o con histerectomía, salpingectomía bilateral u ovariectomía bilateral).
    17.Mujeres en período de lactancia.
    18.Presenta enfermedad, afección, antecedentes quirúrgicos, resultados en exploración física o anomalía en análisis, pasados o en curso y de importancia clínica que, en opinión de investigador, podrían afectar a seguridad de paciente; alterar absorción, distribución, metabolismo o excreción de fármaco de estudio; o perjudicar evaluación de resultados de estudio.
    19.Es analfabeto o por otro motivo no puede o no quiere cumplimentar evaluaciones diarias de ISM-SAF en el diario electrónico. Debe dominar uno de los idiomas disponibles para formulario ISM-SAF y otros cuestionarios sobre CdV.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1 - RP2D in patients with ISM.
    Part 2 - mean change in ISM-SAF TSS.
    Part 3 - long-term safety and efficacy of avapritinib.
    Parte 1- DRF2 en pacientes con MSI.
    Parte 2- cambio medio en la TSS del ISM-SAF.
    Parte 3- seguridad y eficacia a largo plazo de avapritinib.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1 - weekly for the first 4 weeks, then every 4 weeks
    Part 2 - from Baseline to Week 12
    Part 3 - weekly for 4 weeks, then every 4 weeks for 5 months, and then every 3 months, for a total of 2 years from C1D1; patients still on study after 2 years will have visits every 6 months (24 weeks) for a total study duration of 5 years, inclusive of Part 1 and Part 2
    Parte 1 - semanal en las 4 primeras semanas, a partir de ahí cada 4 semanas
    Parte 2 - desde el inicio hasta semana 12
    Parte 3 - semanal durante 4 semanas, a partir de ahí cada 4 semanas durante 5 meses, y después cada 3 meses, para un total de 2 años desde D1C1; los pacientes todavía en estudio después de 2 años tendrán visitas cada 6 meses (24 semanas) para una duración total de estudio de 5 años, inluyendo parte 1 y parte 2.
    E.5.2Secondary end point(s)
    Part 1 and Part 2
    • Change in measures of MC burden:
    o Serum tryptase.
    o KIT D816V allele burden in blood.
    o BM MCs.
    o Skin MCs in patients with baseline CM.
    • Change in percent body surface area (BSA) involved by CM and change in pigmentation of cutaneous lesions in patients with baseline CM.
    • Change in BSC concomitant medication usage.
    • Change in "lead symptom" score of ISM-SAF from Baseline to Week 12.
    • Proportion of patients with at least 5-point, 10-point, and 15-point reductions in TSS and domain scores of ISM-SAF from Baseline to Week 12.
    • Time to achieve 5-point, 10-point, 15-point, and maximum reductions in TSS and domain scores of ISM-SAF.
    • Change in domain scores and individual symptom scores of ISM-SAF from Baseline to Week 12.
    • Change in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L.
    • Change in number of episodes of anaphylaxis, based on epinephrine use.
    • Safety and tolerability of avapritinib, as assessed by AEs, vital signs, ECGs, and laboratory tests.
    • Pharmacokinetics of avapritinib.
    • Correlations between avapritinib exposure and safety and efficacy endpoints.

    Part 3
    • Change in the following measures of MC burden:
    o Serum tryptase.
    o KIT D816V allele burden in blood.
    o BM MCs (optional).
    o Skin MCs in patients with baseline CM (optional).
    • Change in BSA involved by CM and change in pigmentation of cutaneous lesions in patients with baseline CM.
    • Change in BSC concomitant medication usage.
    • Change in "lead symptom" score of ISM-SAF.
    • Change in TSS, domain scores, and individual symptom scores of ISM-SAF from Part 3 baseline (and from Part 1 and Part 2 baseline for patients receiving same dose of avapritinib in both study parts) to Weeks 12, 24, 36, and 52.
    • Time to achieve 5-point, 10-point, and 15-point, and maximum reductions in TSS and domain scores of ISM-SAF from Part 3 baseline (and from Part 1 and Part 2 baseline for patients receiving same dose of avapritinib in both study parts).
    • Changes in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L.
    • Change in number of episodes of anaphylaxis, based on epinephrine use.
    • Safety and tolerability of avapritinib, as assessed by AEs, vital signs, ECGs, and laboratory tests.
    Parte 1 y Parte 2
    • Cambio en las medidas de carga de MCs:
    o triptasa sérica
    o carga alélica de D816V de KIT en sangre
    o MCs en MO
    o mastocitos en la piel en pacientes con MC inicial
    • Cambio en el porcentaje de superficie corporal afectada por la MC y cambio en la pigmentación de lesiones cutáneas en pacientes con MC inicial.
    • Cambio en el uso de medicación concomitante del MTS.
    • Cambio en la puntuación del “síntoma principal” del ISM-SAF desde el inicio hasta la semana 12.
    • Proporción de pacientes con reducciones de al menos 5, 10 y 15 puntos en la TSS y en las puntuaciones de dominios del ISM-SAF desde el inicio hasta la semana 12.
    • Tiempo hasta conseguir reducciones de 5, 10, 15 puntos y máximas en la TSS y en las puntuaciones de dominios del ISM-SAF.
    • Cambio en las puntuaciones de dominios y puntuaciones del síntoma individual del ISM-SAF desde el inicio hasta la semana 12.
    • Cambio en MC-QoL, PGIS, SF-12, PGIC y EQ-5D-5L.
    • Cambio en el número de episodios de anafilaxia, según el uso de epinefrina.
    • Seguridad y tolerabilidad de avapritinib, evaluadas mediante los AA, constantes vitales, ECG y pruebas analíticas.
    • Farmacocinética de avapritinib.
    • Correlación entre la exposición a avapritinib y los criterios de valoración de la seguridad y la eficacia.
    Parte 3
    • Cambios en los siguiente parámetros de la carga de MCs:
    o triptasa sérica
    o carga alélica de D816V de KIT en sangre
    o MCs en MO (opcional)
    o mastocitos en la piel en pacientes con MC inicial (opcional)
    • Cambio en la superficie corporal afectada por la MC y cambio en la pigmentación de lesiones cutáneas en pacientes con MC inicial.
    • Cambio en el uso de medicación concomitante del MTS.
    • Cambio en la puntuación del “síntoma principal” del ISM-SAF.
    • Cambio en la TSS, puntuaciones de dominios y puntuaciones de síntomas individuales del ISM-SAF desde el inicio de la Parte 3 (y desde el inicio de la Parte 1 y de la Parte 2 para pacientes que reciben la misma dosis de avapritinib en ambas partes del estudio) hasta las semanas 12, 24, 36 y 52.
    • Tiempo hasta conseguir reducciones de 5, 10, 15 puntos y máximas en la TSS y en las puntuaciones de dominios del ISM-SAF desde el inicio de la Parte 3 (y desde el inicio de la Parte 1 y de la Parte 2 para pacientes que reciben la misma dosis de avapritinib en ambas partes del estudio).
    • Cambios en MC-QoL, PGIS, SF-12, PGIC y EQ-5D-5L.
    • Cambio en el número de episodios de anafilaxia, según el uso de epinefrina.
    • Seguridad y tolerabilidad de avapritinib, evaluadas mediante los AA, constantes vitales, ECG y pruebas analíticas.
    E.5.2.1Timepoint(s) of evaluation of this end point
    •Tryptase: Screening, every visit through C3D8 (P1-2); every visit (P3)
    •KIT D816V allele burden: Screening, C1D1/D15, C2D1, C3D8 (P1-2), every 4W until P3 (P1); C1D1, C3D1, every 12W during C6-25, every 24W during C26 through end of study (P3)
    •BM & skin biopsy: Screening, between C3D8 & D15 (P1-2); optional at W52 (P3)
    •Skin photo: Screening, between C3D8 & D15, every 12W until W52 in P3
    •ISM-SAF: daily from baseline to W12 (P1-2); from P3 baseline to W12/24/36/52
    •QoL: each visit through P3 W52
    •Anaphylaxis episode: Screening, throughout study
    •AE & BSC: throughout study
    •Vital signs, hematology & chemistry: every visit until EOT
    •ECG: Screening, C1D1, C2D1, C3D8 (P1-2), between C3D8 & D15, D1 of every C (P1); D1 of every P3 visit
    •PK: before & after study drug dosing (P1-2)
    •Triptasa:Selección,cada visita hasta C3D8 (P1-2);cada visita (P3)
    •KIT D816V carga alélica:Selección,C1D1/D15,C2D1,C3D8 (P1-2),cada 4S hasta P3 (P1);C1D1, C3D1, cada 12S durante C6-25, cada 24S durante C26 hasta end of study (P3)
    •Biopsia MO y piel:Selección,entre C3D8 y D15 (P1-2); opcional en S52 (P3)
    •Foto de piel:Selección,entre C3D8 y D15,cada 12S hasta S52 en P3
    •ISM-SAF:diario desde basal hasta S12 (P1-2);desde basal de P3 hasta S12/24/36/52
    •QoL:cada visita hasta P3 S52
    •Episodio de anafilaxis:Selección,a lo largo de estudio
    •AA y medic. concom.:a lo largo de estudio
    •CVs, hematología y BQ:cada visita hasta FdE
    •ECG:Selección,C1D1,C2D1,C3D8 (P1-2),entre C3D8 y D15,D1 de cada C (P1);D1 de cada visita en P3
    •PK:antes y después de medicación de estudio (P1-2)
    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 Yes
    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 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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 EEA14
    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
    Belgium
    Canada
    Denmark
    Germany
    Italy
    Netherlands
    Spain
    United Kingdom
    United States
    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
    The end of the study is defined as the time that the last patient completes his/her last visit (LPLV), including assessments performed as part of safety follow-up.
    El fin de estudio se define como el momento en el que el ultimo paciente completa su última visita (LPLV), incluidas las valoraciones hechas como parte del seguimiento de seguridad.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 60
    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)
    Normal standard of care.
    Estándar de tratamiento normal.
    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 Decision2019-01-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-22
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA