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    Summary
    EudraCT Number:2017-002326-21
    Sponsor's Protocol Code Number:GEM-SELIBORDARA
    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:2018-02-12
    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 number2017-002326-21
    A.3Full title of the trial
    An Open-label, Multicenter, Phase 2 trial of selinexor (KPT-330), bortezomib and low-dose dexamethasone plus daratumumab (SELIBORDARA) for the treatment of patients with refractory or relapsed and refractory multiple myeloma
    Ensayo abierto, multicéntrico, de fase 2 de selinexor (KPT-330), bortezomib y dosis baja de dexametasona más daratumumab (SELIBORDARA) para el tratamiento de pacientes con mieloma múltiple en recaída y/o refractario
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Trial with selinexor (KPT-330), bortezomib and low-dose dexamethasone plus daratumumab (SELIBORDARA) for the treatment of patients with refractory or relapsed and refractory multiple myeloma
    Ensayo clínico de selinexor (KPT-330), bortezomib y dosis baja de dexametasona más daratumumab (SELIBORDARA) para el tratamiento de pacientes con mieloma múltiple en recaída y/o refractario
    A.3.2Name or abbreviated title of the trial where available
    GEM-SELIBORDARA
    GEM-SELIBORDARA
    A.4.1Sponsor's protocol code numberGEM-SELIBORDARA
    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 SponsorFundación PETHEMA
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFundación Pethema
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFundación Pethema
    B.5.2Functional name of contact pointDr. Juan José Lahuerta Palacios
    B.5.3 Address:
    B.5.3.1Street AddressHospital Clínico San Carlos. 2ª Sur. Hematología. - C/ Profesor Martín Lagos s/n
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28040
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491 779 28 76
    B.5.5Fax number+3491 330 33 12
    B.5.6E-mailpethema@pethema.es
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name DARZALEX
    D.2.1.1.2Name of the Marketing Authorisation holderDARZALEX
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDARZALEX
    D.3.4Pharmaceutical form 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 INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.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 VELCADE
    D.2.1.1.2Name of the Marketing Authorisation holderVELCADE
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVELCADE
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBORTEZOMIB
    D.3.9.1CAS number 179324-69-7
    D.3.9.4EV Substance CodeSUB20020
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.5
    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 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 nameSelinexor
    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 INNSELINEXOR
    D.3.9.3Other descriptive nameSELINEXOR
    D.3.9.4EV Substance CodeSUB177942
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with refractory or relapsed and refractory multiple myeloma
    Pacientes con mieloma múltiple en recaída y/o refractario
    E.1.1.1Medical condition in easily understood language
    patients with multiple myeloma
    Pacientes con mieloma múltiple
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary endpoint of the trial is to evaluate the efficacy of the combination selinexor, bortezomib plus low-dose dexamethasone and daratumumab in terms of overall response rate (ORR), including stringent complete responses, complete responses (CR), very good partial responses (VGPR), and partial responses (PR) according to the International Myeloma Working Group Criteria (IMWG). The clinical benefit rate (CR+VGPR+PR+MR) and disease control rate (CR+VGPR+PR+MR+SD) will be also evaluated.
    El objetivo principal del ensayo es evaluar la eficacia de la combinación de selinexor, bortezomib más dexametasona a dosis baja y daratumumab, en términos de tasa de respuesta global (TRG), incluyendo respuesta completa estricta (RCe), respuesta completa (RC), muy buena respuesta parcial (MBRP) y respuesta parcial (RP), de acuerdo con los criterios del International Myeloma Working Group (IMWG). Se evaluará asimismo la tasa de beneficio clínico (RC+MBRP+RP+RM) y la tasa de control de la enfermedad (RC+MBRP+RP+RM+EE).
    E.2.2Secondary objectives of the trial
    - To evaluate the safety and tolerability of the combination, as determined by the incidence of clinical and laboratory toxicities.
    - To evaluate time-to-events data: time to progression, duration of response, progression free survival, and overall survival.
    - Evaluar la seguridad y tolerabilidad de la combinación, de acuerdo con la incidencia de toxicidades clínicas y de laboratorio.
    - Evaluar el tiempo-hasta-los-eventos: tiempo hasta la progresión (THP), duración de la respuesta (DR), supervivencia libre de progresión (SLP), y supervivencia global (SG).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient is, in the investigator’s opinion, willing and able to comply with the protocol requirements.
    2. Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
    3. Patient must be at least 18 years of age.
    4. Patient must have a confirmed diagnosis of symptomatic multiple myeloma and measurable secretory disease, defined as either serum monoclonal protein ≥ 0,5 g/dL or urine monoclonal (light chain) protein ≥ 200 mg/24 hours. For patients in whom measurable disease is performed by serum FLC, the involved FLC should be  10 mg/dL, with an abnormal serum FLC ratio.
    5. Patients must have an ECOG performance status of 0, 1 or 2.
    6. All patients must have received prior treatment with proteasome inhibitors and immunomodulators: A minimum of 2 consecutive cycles of proteasome inhibitors and immunomodulators are required.
    7. Patients must have received ≥ 3 prior lines of therapy and be refractory to the last line of therapy, or
    a. Be double refractory to proteasome inhibitors and immunomodulatory drugs on their most recent therapy, regardless of the prior number lines of therapy.
    b. Patients were thought to be refractory if they had progressed on or within 60 days of treatment with bortezomib and/or lenalidomide.
    8. Patient has the following laboratory values within 14 days before Baseline visit (Day 1 of Cycle 1, before study drug administration): Platelet count ≥ 75 x109/L, hemoglobin ≥ 8.0g/dl and absolute neutrophil count (ANC) ≥ 1.5 x 109/L; lower values may be accepted if clearly are due to bone marrow involvement by multiple myeloma (ANC ≥ 1.0 x 109/L and platelets ≥ 50 x109/L if bone marrow infiltration > 60%). Patients receiving hematopoietic growth factor support, including erythropoietin (EPO), darbepoetin, granulocyte-colony stimulating factor (G-CSF) may continue to do so.
    9. Corrected serum calcium < 14mg/dl.
    10. Aspartate transaminase (AST): ≤ 2.5 x the upper limit of normal, alanine transaminase (ALT): ≤ 2.5 x the upper limit of normal, and total bilirrubin: ≤ 2.0 x the upper limit of normal.
    11. Calculated creatinine clearance ≥ 20 ml per minute, calculated using the formula of Cockroft and Gault:
    (140-Age) • Mass (kg)/(72 • creatinine mg/dL)
    Multiply times 0.85 if the patient is female, or CrCl >20 mL/min as measured by 24-hour urine collection.
    12. Women of childbearing potential must be practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: eg, established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods: condom with spermicidal foam/gel/film/cream/suppository; male partner steritilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of the subject) during and after the study (6 months after the last dose of any component of the treatment regimen).
    13. A woman of childbearing potential must have a negative serum pregnancy test at screening within 10-14 days and 24 hours before commencing treatment. Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods or reliable birth control simultaneously.
    1. El paciente, en opinión del investigador, quiere cumplir todos los requerimientos del protocolo y es capaz de hacerlo.
    2. Antes de la realización de cualquier actividad relacionada con el estudio que no forme parte de los cuidados médicos habituales, el paciente ha otorgado voluntariamente consentimiento informado, y comprende que puede retirar dicho consentimiento en cualquier momento, sin perjuicio con respecto a sus cuidados médicos futuros.
    3. El paciente debe tener al menos 18 años de edad.
    4. El paciente debe tener un diagnóstico confirmado de MM sintomático y enfermedad secretora medible, definida como proteína monoclonal en suero ≥ 0,5 g/dL o proteína monoclonal (cadenas ligeras) en orina ≥ 200 mg/24 h. En los pacientes en los que la enfermedad se determine mediante CLLs en suero, el valor de CLL deberá ser ≥ 10mg/dL, con un cociente kappa/lambda sérico alterado.
    5. Los pacientes deberán tener un valor de 0, 1 o 2 en la escala ECOG de calidad de vida.
    6. Todos los pacientes tienen que haber recibido tratamiento previo con IPs e IMiDs: se requiere un mínimo de dos ciclos consecutivos de IPs e IMiDs.
    7. Los pacientes tienen que haber recibido tres o más líneas de terapia, y haber sido refractarios a la última de ellas, o:
    -a. Ser doblemente refractarios a IPs e IMiDs en su tratamiento más reciente, independientemente del número de terapias previas.
    -b. Se considerará a los pacientes como refractarios si experimentaron progresión dentro de los 60 días posteriores a la finalización de tratamiento con bortezomib y/o lenalidomida.
    8. El paciente presenta los siguientes valores de laboratorio dentro de los 14 días previos a la Visita Basal (Día 1 del Ciclo 1, antes de la administración del fármaco en estudio): recuento de plaquetas ≥75x109/L, hemoglobina ≥8,0 g/dL, y recuento absoluto de neutrófilos (RAN) ≥1,5x109/L; se podrían aceptar valores más bajos si éstos se debieran, claramente, a la afectación medular por MM (RAN ≥1,0x109/L y plaquetas ≥50x109/L si la infiltración en médula ósea >60%). Los pacientes que estén recibiendo factores de crecimiento hematopoyético, incluyendo eritropoyetina (EPO), darbepoetina o factores estimuladores de colonias de granulocitos (G-CSF), pueden continuar con dichas medidas de soporte.
    9. Calcio sérico corregido <14 mg/dL.
    10. Tanto AST como ALT deben ser menores o similares a 2,5 veces su límite superior de normalidad, y la bilirrubina total debe ser menor o igual a dos veces su límite superior de normalidad.
    11. El cálculo del aclaramiento de creatinina (CrCl) debe ser ≥20 mL/minuto, cálculo que se realizará según la fórmula de Cockroft y Gault:
    (140-edad) • peso (kg)/(72 • creatinina (mg/dL))
    El resultado debe multiplicarse por 0,85 en las mujeres, y el CrCl debe ser >20 mL/minuto si se mide en muestras de orina de 24 horas.
    12. Las mujeres fértiles deben utilizar un método de control de natalidad altamente efectivo de acuerdo con las normativas locales de uso de métodos de control del embarazo para personas que participen en estudios clínicos: por ejemplo, el uso implantado de métodos de contracepción hormonales por vía oral, de inyección o implante; colocación de un dispositivo intrauterino o un sistema intrauterino; métodos de barrera: preservativo con espermicida espuma/gel/película/crema/supositorio; esterilización de la pareja masculina (la pareja vasectomizada debe ser la única pareja de la mujer); o abstinencia real (cuando esta sea coherente con las preferencias y estilo de vida habitual). Los métodos de anticoncepción deberán mantenerse durante y después del estudio (seis meses después de la última dosis de cualquier componente del tratamiento).
    13. Una mujer en edad reproductiva debe tener una prueba de embarazo negativa durante el proceso de reclutamiento, entre 10-14 días y 24 horas antes del comienzo del tratamiento. Las mujeres con potencial reproductivo deben comprometerse bien a abstenerse en todo momento de mantener relaciones sexuales heterosexuales; o a usar dos métodos de contracepción fiables simultáneamente.
    E.4Principal exclusion criteria
    1. Subject has received selinexor or daratumumab therapies previously.
    2. Patients who are refractory to daratumumab or CD38 targeting antibody.
    3. Subject has a diagnosis of plasma cell leukemia, primary amyloidosis, monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM).
    4. Subject has previously received autologous stem cell transplantation within 12 weeks before Cycle Day 1, or has received other anti-myeloma treatment within 2 weeks before Cycle 1 Day 1 (with the exception of an emergency use of a short course [maximum 4 days] of corticosteroids).
    5. Subject who had previously received allogeneic stem cell transplantation within the last year or even latter if they have evidence of graft versus host disease.
    6. Subject has peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.
    7. Subject has had any prior or concurrent invasive malignancy (other than myeloma) within 5 years of study start except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, localized prostate adenocarcinoma diagnosed ≥ 3 years and without evidence of biochemical failure, or other cancer for which the subject has undergone potentially curative therapy and has no evidence of that disease for ≥ 5 years.
    8. Subject has had radiation therapy within 28 days of Cycle 1 Day 1.
    9. Subject has meningeal involvement of multiple myeloma.
    10. Subject has known severe chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of severe asthma within 5 years. Subjects with known or suspected COPD or asthma must have a FEV test during screening.
    11. Subjects have known moderate or severe persistent asthma within the past 2 years (see Appendix 8: National Heart, Lung, and Blood Institute (NHLBI) table of asthma severity), or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild ersistene asthma are allowed in the study).
    12. Unstable cardiovascular function:
    a. Symptomatic ischemia, or
    b. Uncontrolled clinically-significant conduction abnormalities (e.g., patients with ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded), or
    c. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3, or
    d. Myocardial infarction (MI) within 3 months.
    13. Patients with uncontrolled hypertension.
    14. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose.
    15. Subject is known to be seropositive for history of human immunodeficiency virus (HIV) or hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg] or antibodies to hepatitis B surface and core antigens [anti HBs and anti-HBc, respectively]) or hepatitis C (anti-HCV antibody positive or HCV-RNA quantitation positive).
    16. Patients with any GI dysfunction who are unable to swallow tablets, or any GI dysfunction that could interfere with absorption of study treatment.
    17. Serious psychiatric or medical conditions that, in the opinion of the investigator, could interfere with treatment.
    1. El paciente ha recibido tratamiento previo con selinexor o daratumumab.
    2. El paciente es refractario a daratumumab o a cualquier anticuerpo dirigido frente a CD38.
    3. El sujeto posee un diagnóstico de leucemia de células plasmáticas, amiloidosis primaria, gammapatía monoclonal de significado indeterminado (GMSI) o MM quiescente (MMq).
    4. El sujeto ha recibido previamente un trasplante autólogo de progenitores hematopoyéticos dentro de las doce semanas anteriores al Día 1 del Ciclo 1, o ha recibido otro tratamiento anti-mieloma dentro de las dos semanas antes del Día 1 del Ciclo 1 (con la excepción del uso de emergencia de un curso corto [cuatro días como máximo de dexametasona 40 mg/día o equivalente] de corticosteroides).
    5. El sujeto ha recibido previamente un trasplante alogénico de progenitores hematopoyéticos dentro del último año, o incluso antes si existen evidencias de enfermedad injerto contra huésped activa.
    6. El sujeto padece neuropatía periférica o dolor por neuropatía de grado 2 o mayor, según se especifica en la Versión 4 de los Criterios Comunes de Terminología para Eventos Adversos del National Cancer Institute (NCI CTCAE).
    7. El sujeto ha padecido previamente, o padece de forma concurrente, cualquier neoplasia invasiva (distinta del mieloma) dentro de los cinco años previos al inicio del estudio, excepto:
    carcinoma basocelular o de células escamosas de la piel, carcinoma in situ de cérvix, adenocarcinoma de próstata localizado diagnosticado hace tres años o más y sin evidencia de fracaso bioquímico, u otro cáncer por el cual el sujeto haya sido sometido a terapia potencialmente curativa y del que no exista evidencia de tal enfermedad al menos durante los últimos cinco años.
    8. El sujeto ha recibido radioterapia dentro de los 28 días previos al Día 1 del Ciclo 1.
    9. El sujeto presenta implicación meníngea del MM.
    10. El sujeto padece EPOC severa (definida como un volumen espiratorio forzado en el primer segundo [FEV1] inferior al 60% del predicho como normal), asma persistente o una historia de asma severo dentro de los últimos cinco años. Los sujetos con EPOC o asma, documentados o en sospecha, deberán someterse a un test de volumen espiratorio forzado durante el proceso de reclutamiento.
    11. Los sujetos han padecido asma persistente moderado o severo documentado, dentro de los últimos dos años (ver Apéndice 8: National Heart, Lung, and Blood Institute (NHLBI), tabla de severidad del asma), o en el momento del reclutamiento padecen asma no controlado en cualquier estadio de clasificación (no debe olvidarse que los sujetos que padecen asma intermitente controlado o asma persistente moderado controlado en el momento del reclutamiento, sí pueden participar en el estudio).
    12. Función cardiovascular inestable:
    a. Isquemia sintomática, o
    b. Anomalías en la conducción clínicamente relevantes y no controladas (p.ej., se excluirá a los pacientes con taquicardia ventricular que tomen antiarrítmicos; no se excluirá a los pacientes con bloqueo auriculoventricular [AV] de primer grado o bloqueo fascicular anterior izquierdo (BFAI)/bloqueo de la rama derecha del haz de His (BRDHH), o
    c. Insuficiencia cardíaca congestiva (ICC) de clase ≥3 de la clasificación funcional de la New York Heart Association (NYHA), o
    d. Infarto agudo de miocardio (IAM) en los tres meses previos al comienzo del tratamiento del estudio.
    13. Pacientes con hipertensión arterial no controlada.
    14. Infección activa no controlada que requiera antibióticos, antivirales o antifúngicos por vía parenteral, dentro de la semana previa a la administración de la primera dosis de los fármacos de estudio.
    15. El sujeto es seropositivo para los virus de la inmunodeficiencia humana (VIH) o de la hepatitis B (en este caso, documentado mediante un test positivo para el antígeno de superficie de la hepatitis B [HBsAg] o por la detección de anticuerpos dirigidos frente a HBsAg o frente a antígenos del core de la hepatitis B [HBcAg]: anti-HBs y anti-HBc, respectivamente), o de la hepatitis C (prueba positiva de detección de anticuerpos frente al virus de la hepatitis C [VHC] o cuantificación positiva de RNA del VHC).
    16. El paciente padece cualquier trastorno gastrointestinal que le impida ingerir comprimidos, o cualquier trastorno gastrointestinal que pueda interferir con la absorción del tratamiento en estudio.
    17. El paciente presenta una condición psiquiátrica o médica lo suficientemente seria para que, en opinión del investigador, esta pueda interferir con el tratamiento.
    E.5 End points
    E.5.1Primary end point(s)
    The primary statistical analysis of efficacy will be performed on ORR (achievement of CR or PR) for the overall ITT population and PP population, with supportive data provided by duration of response; The CBR and DCR will be also evaluated, including the evaluation of patients in Minor Response and Stable disease as well.
    Duration of response will be described using the stratified KM method, with strata defined by prior exposure to the different proteasome inhibitors and Immunomodulatory drugs, cytogenetic abnormalities as well as by ISS stage III versus stage I or II, including an estimate of the median, as well as the 25th and 75th percentiles, along with two-sided 95% confidence intervals.
    El principal análisis estadístico de la eficacia se centrará en la TRG (alcanzar RC o RP) para la población global del AIT y para la población global del APP, con datos complementarios adicionales que proporcionarán la DR; también se determinarán la TBC y la TCE, incluyendo la evaluación de los pacientes en RM y EE.
    Se describirá la DR empleando el método de Kaplan-Meier estratificado, con los estratos definidos por la exposición previa a diferentes IPs e IMiDs, alteraciones citogenéticas, así como por estadio III según el International Staging System (ISS) vs. estadios I o II, e incluyendo una estimación de la mediana, así como los percentiles 25 y 75, junto con IC al 95% (bilateral).
    E.5.1.1Timepoint(s) of evaluation of this end point
    54 moths
    54 meses
    E.5.2Secondary end point(s)
    Key secondary endpoints, including, PFS and OS will be statistically evaluated using appropriate confidence intervals. Statistical tests will be performed at the one-sided, 0.025 level. The duration of response (DOR) is defined as the duration of time measured from when response criteria were first met until the first date of recurrence or PD or death. PFS will be assessed using KM methods and OS will be assessed based on the same KM approach as used for PFS.
    Duration of response will be calculated, for patients achieving response (ORR), as the duration from the date when first evidence of objective disease response was achieved based on IMWG criteria, until the first date of recurrence, PD, or death. The start of DCR will be based on the date of first receipt of treatment. The duration of response for each respective type of response will be regarded as descriptive adjuncts to the analyses of response rates. Analysis of duration of each response type will be performed using stratified KM methods.
    Los objetivos secundarios clave, que incluyen SLP y SG, se evaluarán estadísticamente empleando los intervalos de confianza apropiados. Las pruebas estadísticas se realizarán al nivel 0,025 unilateral. La DR se define como la duración del periodo comprendido entre el momento en el que por primera vez se alcanzaron criterios de respuesta de la enfermedad hasta la primera fecha de recurrencia, PE o muerte. La SLP se determinará mediante métodos basados en Kaplan-Meier, y la SG también mediante este tipo de aproximación.
    La DR se calculará, en los pacientes que consigan una respuesta (TRG), como la duración del periodo entre la fecha en la que se observó la primera evidencia de respuesta objetiva de la enfermedad, según los criterios IMWG, y la fecha de la primera recurrencia, PE o muerte. El inicio de la TCE se establecerá en la fecha de la primera dosis del tratamiento. La DR para cada tipo concreto de respuesta se tratará como información descriptiva adjunta a los análisis de las tasas de respuesta. Los análisis de la duración de cada tipo de respuesta se llevará a cabo según métodos de Kaplan-Meier con estratificación.
    E.5.2.1Timepoint(s) of evaluation of this end point
    54 months
    54 meses
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.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 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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned15
    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
    LPLV
    Última visita último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months54
    E.8.9.1In the Member State concerned days
    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: 31
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 31
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state62
    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)
    According to clinical practice
    Acorde a práctica clínica
    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 Decision2018-05-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-27
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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