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    Summary
    EudraCT Number:2018-002761-19
    Sponsor's Protocol Code Number:OP201
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2019-08-09
    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 number2018-002761-19
    A.3Full title of the trial
    An Open-Label, Phase 1/2 Study of Melflufen and Dexamethasone for Patients with AL Amyloidosis Following at Least One Prior Line of Therapy
    Estudio abierto de fase 1/2 de melflufen y dexametasona en pacientes con amiloidosis AL después de como mínimo una línea de tratamiento previo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    It is an early clinical trial to assess a new drug (Melflufen) when given
    together with a steroid (Dexamethasone) in the treatment of patients with a disease called the AL Amyloidosis.
    Patients should also have received treatment in the past for the disease.
    Es un ensayo clínico de fase temprana para evaluar una nueva medicina (melflufen) cuando esta se administra junto con un esteroide (dexametasona) en el tratamiento de pacientes con una enfermedad llamada amiloidosis AL.
    Dichos pacientes deben de haber sido tratados ya en el pasado contra esta enfermedad.
    A.4.1Sponsor's protocol code numberOP201
    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 SponsorOncopeptides AB
    B.1.3.4CountrySweden
    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 supportOncopeptides AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOncopeptides AB
    B.5.2Functional name of contact pointClinical Trials Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressVästra Trädgårdsgatan 15
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post codeSE-111 53
    B.5.3.4CountrySweden
    B.5.6E-mailtrials@oncopeptides.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 nameMelflufen
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmelphalan fulfenamide hydrochloride
    D.3.9.1CAS number 380449-54-7
    D.3.9.3Other descriptive nameMELFLUFEN
    D.3.9.4EV Substance CodeSUB22033
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 Dexamethasone 4 mg JENAPHARM
    D.2.1.1.2Name of the Marketing Authorisation holdermibe GmbH Arzneimittel
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameDexamethasone
    D.3.2Product code H02AB02
    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 INNDEXAMETHASONE
    D.3.9.1CAS number 50-02-2
    D.3.9.4EV Substance CodeSUB07017MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 AL Amyloidosis
    Pacientes con amiloidosis AL
    E.1.1.1Medical condition in easily understood language
    Patients with AL Amyloidosis
    Pacientes con amiloidosis AL
    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 10002022
    E.1.2Term Amyloidosis
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1
    •To explore the safety and tolerability
    •To identify recommended Phase 2 dose (RP2D).
    Phase 2
    •To evaluate the hematologic ORR after 4 cycles at the RP2D determined in Phase 1
    Fase 1
    • Explorar la seguridad y la tolerabilidad
    • Identificar la dosis recomendada para la fase 2 (DRF2)
    Fase 2
    • Evaluar la TRG hematológica después de 4 ciclos con la DRF2 determinada en la fase 1
    E.2.2Secondary objectives of the trial
    Phase 1
    •To assess pharmacokinetic profile of melflufen in this patient population
    •To assess best hematologic response
    •To assess duration of hematologic response
    •To assess the proportion of organ system responses
    •To assess duration of organ system responses
    •To assess hematologic ORR
    •To assess time to next AL amyloidosis treatment
    •To assess OS

    Phase 2

    •To assess safety and tolerability
    •To assess best hematologic response
    •To assess duration of hematologic response
    •To assess the proportion of organ system responses
    •To assess duration of organ system responses
    •To assess time to next AL amyloidosis treatment
    •To assess OS

    Exploratory

    •To assess MRD
    Fase 1
    • Evaluar el perfil farmacocinético de melflufen en esta población de pacientes
    • Evaluar la mejor respuesta hematológica
    • Evaluar la duración de la respuesta hematológica
    • Evaluar la proporción de respuestas por aparato y sistema
    • Evaluar la duración de las respuestas por aparato y sistema
    • Evaluar la TRG hematológica
    • Evaluar el tiempo transcurrido hasta el siguiente tratamiento para la amiloidosis AL
    • Evaluar la SG

    Fase 2
    • Evaluar la seguridad y la tolerabilidad
    • Evaluar la mejor respuesta hematológica
    • Evaluar la duración de la respuesta hematológica
    • Evaluar la proporción de respuestas por aparato y sistema
    • Evaluar la duración de las respuestas por aparato y sistema
    • Evaluar el tiempo transcurrido hasta el siguiente tratamiento para la amiloidosis AL
    • Evaluar la SG

    Exploratorios
    • Evaluar la ERM
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female, age 18 years or older at the time of signing the informed consent.
    2. Proven histochemical diagnosis of AL amyloidosis based on tissue specimens with Congo red staining with exhibition of an apple-green birefringence confirmed with appropriate method of typing, e.g. mass spectrometry, immunofluorescence or immunohistochemistry (previous aspirate/biopsy tissue specimen result acceptable).
    3. At least one prior line of therapy, defined as either one non-transplant regimen, one ASCT, or one regimen of induction therapy followed by a single ASCT (without hematologic progression between induction and ASCT). No more than 4 cycles of melphalan containing chemotherapy is allowed.
    4. Measurable hematologic disease as defined by serum differential free light chain (dFLC) concentration ≥ 20 mg/L (dFLC is the difference between amyloid forming [involved] and non-amyloid forming [uninvolved] FLC).
    5. Objectively measurable (cardiac, and/or renal and/or liver) organ amyloid involvement, as defined below (amyloid involvement of at least 1 required). See also Appendix 9:
    a. Cardiac involvement: mean wall thickness >12 mm on echocardiogram, with no other cardiac cause or an elevated NT-ProBNP (>332 ng/L) in the absence of renal failure or atrial fibrillation.
    b. Renal involvement is defined as proteinuria (predominantly albumin) >0.5 g/day in a 24-hour urine collection.
    c. Hepatic involvement: Total liver span >15 cm in the absence of heart failure, or alkaline phosphatase >1.5 times institutional upper limit of normal (ULN).
    Amyloid involvement of other organ systems is allowed, but not required.
    6. ECOG performance status ≤ 2. See Appendix 5.
    7. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test (See Appendix 4).
    8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information.
    9. Less than 30% plasma cells in bone marrow aspirate or biopsy.
    10. 12-lead screening ECG with QRS < 120 msec, PR < 220 msec and QTcF interval of ≤ 470 msec calculated by Fridericia Formula (Appendix 12).
    11. Echocardiogram (ECHO) with left ventricular ejection fraction (LVEF) ≥ 45%.
    12. The following laboratory results must be met:
    • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (1.5 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of therapy)
    • Platelet count ≥ 100,000 cells/mm3 (100 x 109/L) without required transfusions during the 10 days prior to initiation of therapy).
    • Hemoglobin ≥ 9.0 g/dl (RBC transfusions are permitted).
    • Total Bilirubin ≤ 1.5 x ULN. Higher value may be accepted in participants diagnosed with Gilbert syndrome, if approved by the medical monitor.
    • Alkaline phosphatase ≤ 3.5 x ULN.
    • AST and ALT ≤ 1.5 x ULN.
    • Renal function: Estimated GFR (eGFR) by CKD-EPI formula ≥ 45 mL/min (Appendix 11). A lower value may be acceptable after consultation and approval of the medical monitor.
    13. Male participant agrees to use contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 90 days after the last dose of melflufen and refrain from donating sperm during this period.
    OR
    Female participant meets one of the following conditions:
    i. Not of child bearing potential as defined in Appendix 4
    ii. Not currently pregnant or breastfeeding and agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and for at least 30 days after the last dose of melflufen.
    1. Pacientes varones o mujeres con al menos 18 años de edad en el momento de la firma del consentimiento informado.
    2. Diagnóstico de amiloidosis AL demostrado histoquímicamente basándose en las muestras tisulares mediante tinción con rojo Congo en las que se muestre una birrefringencia verde manzana confirmada mediante el método de tipificación apropiado, por ejemplo, espectrometría de masas, inmunofluorescencia o inmunohistoquímica (es aceptable el resultado en una muestra tisular de biopsia/aspirado anterior).
    3. Uso de al menos una línea anterior de tratamiento, lo que se define bien como un tratamiento sin trasplante, un ATCM o un tratamiento de inducción seguido de un único ATCM (sin progresión hematológica entre el tratamiento de inducción y el ATCM). No se permite el uso de más de 4 ciclos de quimioterapia con melfalán.
    4. Enfermedad hematológica mensurable, definida como una concentración sérica diferencial de cadenas ligeras libres (CLLd, que es la diferencia entre las CLL formadoras de amiloides [implicadas] y las que no forman amiloides [no implicada]) ≥ 20 mg/l.
    5. Afectación amiloide de algún órgano (corazón, riñón o hígado) mensurable de forma objetiva, según se define a continuación (se exige la afectación amiloide de al menos uno). Véase también el Anexo 9:
    a. Afectación cardíaca: espesor medio de la pared > 12 mm en el ecocardiograma, sin ninguna otra causa cardíaca o concentración elevada de NT-ProBNP (> 332 ng/l) en ausencia de insuficiencia renal o de fibrilación auricular.
    b. La afectación renal se define como proteinuria (predominantemente albúmina) > 0,5 g/día en la recogida de orina de 24 horas.
    c. Afectación hepática: Tamaño total del hígado > 15 cm en ausencia de insuficiencia cardíaca o fosfatasa alcalina > 1,5 veces el límite superior de la normalidad (LSN) del centro. Se permite la afectación amiloide de otros aparatos y sistemas, pero no se exige.
    6. Estado funcional ECOG ≤ 2. Véase el Anexo 5.
    7. Las mujeres en edad fértil (MEF) deben haber obtenido un resultado negativo en la prueba de embarazo en suero u orina (véase el Anexo 4).
    8. Capacidad de comprender la finalidad y los riesgos del estudio y de dar el consentimiento informado, firmado y fechado, y la autorización para usar información médica protegida.
    9. Presencia de menos de un 30 % de células plasmáticas en un aspirado o biopsia de la médula ósea.
    10. ECG de cribado de 12 derivaciones con QRS < 120 ms, PR < 220 ms e intervalo QTcF ≤ 470 ms calculado mediante la fórmula de Fridericia (Anexo 12).
    11. Ecocardiograma (ECO) con fracción de eyección ventricular izquierda (FEVI) ≥ 45 %.
    12. Deben cumplirse los resultados analíticos que se indican a continuación:
    • Recuento absoluto de neutrófilos (RAN) ≥ 1500 células/mm3 (1,5 × 109/l; no se pueden utilizar factores de crecimiento dentro de los 10 días [14 días en el caso del pegfilgrastim] anteriores al inicio del tratamiento)
    • Recuento de plaquetas ≥ 100 000 células/mm3 (100 × 109/l; sin necesidad de transfusiones durante los 10 días anteriores al inicio del tratamiento).
    • Hemoglobina ≥ 9,0 g/dl (se permiten las transfusiones de eritrocitos).
    • Bilirrubina total ≤ 1,5 × LSN. Puede aceptarse un valor más elevado en los participantes con diagnóstico de síndrome de Gilbert, si lo aprueba el monitor médico.
    • Fosfatasa alcalina ≤ 3,5 × LSN.
    • AST y ALT ≤ 1,5 × LSN.
    • Funcionalidad renal: TFG estimada (TFGe) por la fórmula CKD-EPI ≥ 45 ml/min (Anexo 11). Puede ser aceptable un valor inferior después de consultar con el monitor médico y recibir su aprobación.
    13. Los hombres participantes aceptan el uso de anticonceptivos según se indica en el Anexo 4 de este protocolo durante el período de tratamiento y durante al menos los 90 días siguientes a la administración de la última dosis de melflufen y aceptan abstenerse de donar esperma durante este período O BIEN
    La mujer participante cumple una de las condiciones que se indican a continuación:
    i. No estar en edad fértil según se define en el Anexo 4
    ii. No estar en este momento embarazada o en período de lactancia y aceptar seguir las indicaciones anticonceptivas en el Anexo 4 durante el período de tratamiento y durante al menos los 30 días siguientes a la administración de la última dosis de melflufen.
    E.4Principal exclusion criteria
    1. Amyloidosis due to known mutations of the transthyretin gene or presence of another non-AL amyloidosis.
    2. Evidence of gastro-intestinal bleeding
    • Frank bleeding within 6 months prior to initiation of therapy.
    • Positive feces-hemoglobin/ fecal occult blood test within 6 months prior to initiation of therapy if clinically relevant. In case of a positive test within the last 6 months, a colonoscopy is required to exclude clinically relevant conditions.
    3. Cardiac risk stage 3 with NT-pro-BNP >5000 pg/mL (Appendix 7).
    4. Low platelets values with evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. unable to maintain a platelet count ≥100,000 cells/mm3 [100 x 109/L]).
    5. Medically documented cardiac syncope, NYHA (Appendix 8) Class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant ventricular arrhythmias, or atrioventricular (AV) block
    6. Clinically significant finding on 24 h Holter recording performed at screening, including but not limited to AV block (with the exception of Mobitz type I that is permitted), intermittent bundle branch block, ventricular arrythmias and sign of sick sinus syndrome.
    7. Severe (symptomatic) orthostatic hypotension (a decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within 3 minutes of standing compared with blood pressure from the supine position. See Section 8.3.2 for details on the assessment of orthostatic hypotension)
    8. Clinically significant factor X deficiency (in investigator’s opinion)
    9. Clinically important autonomic disease (in investigator’s opinion)
    10. Any medical conditions that, in the Investigator’s opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study.
    11. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of treatment. Other wash out period may be considered after consultation and approval of the medical monitor.
    12. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast, and very-low and low risk prostate cancer in active surveillance as defined in NCCN Guideline: Prostate Cancer (NCCN 2019).
    13. Pregnant or breast-feeding females.
    14. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation.
    15. Known HIV or active hepatitis B or C viral infection.
    16. Concurrent symptomatic multiple myeloma (symptomatic defined as presence of bone lesion, extramedullary plasmacytoma or hypercalcemia (Rajkumar et al. 2014))
    17. POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes].
    18. Previous cytotoxic therapies, including cytotoxic investigational agents, within 3 weeks (6 weeks for nitrosoureas) prior to start of study treatment (Prednisone up to, but no more than, 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted, but dose should be stable for at least 7 days prior to study treatment). Monoclonal antibodies (mAbs) within 4 weeks. Concomitant immunotherapy, investigational therapy, and anticoagulation therapy are not permitted (low dose acetylsalicylic acid (ASA) permitted).
    19. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia, or neuropathy without pain, are permitted).
    20. Prior autologous or allogeneic stem cell transplant within 12 weeks of initiation of therapy.
    21. Prior allogeneic stem cell transplant with active graft-versus-host- disease (GVHD).
    22. Prior major surgical procedure or radiation therapy within 4 weeks of the first dose of study treatment.
    23. Known intolerance to steroid therapy.
    1. Amiloidosis debida a mutaciones conocidas del gen de la transtiretina o presencia de otra amiloidosis que no sea AL.
    2. Signos de hemorragia gastrointestinal
    • Hemorragia patente en los 6 meses anteriores al inicio del tratamiento.
    • Resultado positivo en la prueba de hemoglobina/sangre oculta en las heces en los 6 meses anteriores al inicio del tratamiento, si fuera clínicamente relevante. En el caso de que se haya obtenido un resultado positivo en alguna prueba en los 6 meses inmediatamente anteriores, es necesario realizar una colonoscopia para excluir trastornos clínicamente relevantes.
    3. Estadio 3 de riesgo cardíaco con NT-proBNP > 5000 pg/ml (Anexo 7).
    4. Valores de plaquetas bajos con signos de hemorragia mucosa o interna, o resistencia a las transfusiones de plaquetas (es decir, incapacidad para mantener una cantidad de plaquetas ≥ 100 000 células/mm3 [100 × 109/l]).
    5. Síncope cardíaco médicamente documentado, insuficiencia cardíaca congestiva de clase 3 o 4 según NYHA (Anexo 8), infarto de miocardio en los 6 meses anteriores, angina de pecho inestable, arritmia ventricular clínicamente significativa o bloqueo auriculoventricular (AV)
    6. Resultado clínicamente significativo en el registro Holter de 24 h obtenido en el momento de la selección incluyendo, entre otros, el bloqueo AV (a excepción del tipo I de Mobitz, que se permite), el bloqueo de rama (hemibloqueo ventricular) intermitente, la arritmia ventricular y los signos de síndrome de disfunción sinusal.
    7. Hipotensión ortostática intensa (sintomática, es decir, una reducción en la presión arterial sistólica de 20 mm Hg o una reducción de la presión arterial diastólica de 10 mm Hg en los 3 minutos en bipedestación en comparación con la presión arterial obtenida en posición supina. Véase la Sección 8.3.2 para obtener más detalles sobre la determinación de la hipotensión ortostática)
    8. Deficiencia clínicamente significativa de factor X (en opinión del investigador)
    9. Enfermedad autonómica clínicamente importante (en opinión del investigador)
    10. Cualquier afección médica que, en opinión del investigador, suponga un riesgo excesivo para el paciente o pueda afectar negativamente a su participación en este estudio.
    11. Infección activa conocida que requiera tratamiento antiinfeccioso por vía parenteral u oral durante los 14 días anteriores al inicio del tratamiento. Puede sopesarse otro período de reposo farmacológico después de consultar con el monitor médico y de recibir su aprobación.
    12. Diagnóstico de otra neoplasia maligna o que haya requerido tratamiento dentro de los 3 años anteriores, excepto el carcinoma basocelular o espinocelular, el carcinoma in situ del cuello uterino o de mama tratados adecuadamente, o el cáncer de próstata de riesgos muy bajo y bajo en vigilancia activa, según se define en las Directrices de la NCCN: Cáncer de próstata (NCCN 2019).
    13. Mujeres embarazadas o en período de lactancia.
    14. Enfermedad psiquiátrica grave, alcoholismo activo o toxicomanía que puedan impedir o generar confusión a la hora de evaluar el cumplimiento o el seguimiento.
    15. Infección vírica conocida por el VIH o de hepatitis B o C activa.
    16. Mieloma múltiple sintomático simultáneo (se define “sintomático” como presencia de una lesión ósea, plasmacitoma extramedular o hipercalcemia [Rajkumar et al. 2014])
    17. Síndrome POEMS (discrasia de células plasmáticas con polineuropatía, visceromegalia, endocrinopatía, proteína monoclonal [proteína M] y cambios en la piel).
    18. Tratamientos citotóxicos anteriores, incluidos agentes citotóxicos en fase de investigación, en las 3 semanas (6 semanas en el caso de las nitrosoureas) anteriores al inicio del tratamiento del estudio (se permite el uso de una dosis de prednisona de hasta 10 mg [pero no más] cada día por vía oral o su equivalente para el tratamiento de los síntomas de las comorbilidades, pero la dosis debería mantenerse estable durante al menos los 7 días anteriores al tratamiento del estudio). Anticuerpos monoclonales (Acm) en las 4 semanas anteriores. No se permite el uso de inmunoterapia concomitante, tratamiento en fase de investigación ni tratamiento anticoagulante (ácido acetilsalicílico [AAS] en dosis bajas).
    19. Efectos secundarios residuales de tratamientos anteriores de grado > 1 antes del inicio del tratamiento (se permiten la alopecia o la neuropatía sin dolor).
    20. Auto- o alotrasplante de células madre dentro de las 12 semanas anteriores al inicio del tratamiento.
    21. Alotrasplante de células madre anterior con enfermedad de injerto contra huésped (EICH) activa.
    22. Procedimiento quirúrgico mayor o radioterapia en las 4 semanas anteriores a la administración de la primera dosis del tratamiento del estudio.
    23. Intolerancia conocida al tratamiento con corticoesteroides.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1
    • Frequency and grade of adverse events (AE) and laboratory values
    • Dose-Limiting Toxicity (DLT) during Cycle 1 up to a maximum dose of melflufen of 40 mg
    Phase 2
    • The proportion of participants who achieve a hematologic Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR)
    Fase 1
    Frecuencia y grado de los acontecimientos adversos (AA) y los valores analíticos
    Toxicidad limitante de la dosis (TLD) durante el ciclo 1 hasta una dosis máxima de 40 mg de melflufen
    Fase 2
    Proporción de participantes que logran una respuesta completa (RC), respuesta parcial muy buena (RPMB) o respuesta parcial (RP) hematológicas
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the course of the study
    Durante el curso del estudio
    E.5.2Secondary end point(s)
    Phase 1
    • Melphalan plasma concentration post melflufen administration
    • Best hematologic response (CR, VGPR, PR, NR, or PD)
    • Duration of hematologic response (CR, VGPR, PR)
    • Proportion of participants with kidney, cardiac or liver response, respectively
    • Duration of organ system specific responses (separately for kidney, cardiac, and liver)
    • The proportion of participants who achieve a hematologic CR, VGPR, or PR
    • Time to next AL amyloidosis treatment
    • OS
    Phase 2
    • Frequency and grade of AEs and laboratory values
    • Best hematologic response (CR, VGPR, PR, NR, or PD)
    • Duration of hematologic response (CR, VGPR, PR)
    • Proportion of participants with kidney, cardiac or liver response, respectively
    • Duration of organ system specific responses (separately for kidney, cardiac, and liver)
    • Time to next AL amyloidosis treatment
    • OS
    Fase 1
    • Concentración plasmática de melfalán tras la administración de melfuflen
    • Mejor respuesta hematológica (RC, RPMB, RP, SR o PE)
    • Duración de la respuesta hematológica (RC, RPMB, RP)
    • Proporción de participantes con respuesta renal, cardíaca o hepática, respectivamente
    • Duración de las respuestas de cada aparato y sistema específico (riñones,
    corazón e hígado por separado)
    • Proporción de participantes que logran una RC, RPMB o RP hematológicas
    • Tiempo transcurrido hasta el siguiente tratamiento para la amiloidosis AL
    • SG

    Fase 2
    • Frecuencia y grado de los AA y los valores analíticos
    • Mejor respuesta hematológica (RC, RPMB, RP, SR o PE)
    • Duración de la respuesta hematológica (RC, RPMB, RP)
    • Proporción de participantes con respuesta renal, cardíaca o hepática,
    respectivamente
    • Duración de las respuestas de cada aparato y sistema específico (riñones, corazón e hígado por separado)
    • Tiempo transcurrido hasta el siguiente tratamiento para la amiloidosis AL
    • SG
    E.5.2.1Timepoint(s) of evaluation of this end point
    During the course of the study
    Durante el curso del estudio
    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) 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 in new patient population
    Estudio de ajuste de dosis en nueva población de pacientes
    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 EEA9
    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
    Czech Republic
    France
    Germany
    Greece
    Israel
    Italy
    Norway
    Poland
    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
    LPLV
    UPUV (último paciente última visita)
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In 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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 46
    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)
    Standard of Care.
    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 Decision2020-02-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-27
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
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