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    Summary
    EudraCT Number:2018-000264-28
    Sponsor's Protocol Code Number:bb2121-MM-002
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2018-08-07
    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 number2018-000264-28
    A.3Full title of the trial
    A Phase 2, Multi-cohort, Open-label, Multi-center Study to Determine the Efficacy and Safety of bb2121 in Subjects with Relapsed and Refractory Multiple Myeloma and in Subjects With High-Risk Multiple Myeloma Having Progressed Within One Year of Initial Treatment (KarMMa-2)
    Estudio fase II con varias cohortes, abierto, multicéntrico para determinar la eficacia y la seguridad del bb2121 en pacientes con mieloma múltiple en recaída y refractario, y en pacientes con mieloma múltiple de alto riesgo que han progresado durante un año desde el tratamiento inicial (KarMMa-2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the efficacy and safety of bb2121 in people who have Myeloma that is not responsive after treatment or who had Myeloma which has returned after a period of treatment.
    Estudio para evaluar la eficacia y la seguridad de bb2121 en pacientes que tienen un mieloma que no responde al tratamiento o que han tenido un mieloma que ha reaparecido tras un periodo de tratamiento.
    A.4.1Sponsor's protocol code numberbb2121-MM-002
    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 SponsorCelgene 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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1888260 1599
    B.5.5Fax number+1913266 0394
    B.5.6E-mailClinicalTrialDisclosure@celgene.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/17/1863
    D.3 Description of the IMP
    D.3.1Product nameAutologous T lymphocyte-enriched population of cells transduced with a lentiviral vector
    D.3.2Product code bb2121
    D.3.4Pharmaceutical form 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 INNAutologous CD3+ T Cells Expressing BCMA Chimeric Antigen Receptor
    D.3.9.3Other descriptive namebb2121
    D.3.9.4EV Substance CodeSUB190570
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberEMA/758319/2016
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    Relapsed and Refractory Multiple Myeloma and High-Risk Multiple Myeloma Having Progressed Within One Year of Initial Treatment
    Mieloma múltiple en recaída y refractario, y Mieloma múltiple de alto riesgo que ha progresado durante un año desde el tratamiento inicial
    E.1.1.1Medical condition in easily understood language
    Cancer of the bone marrow that recurs or is resistant to treatment
    Cáncer de médula ósea que reaparece o es resistente al tratamiento
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level HLT
    E.1.2Classification code 10028229
    E.1.2Term Multiple myelomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10067095
    E.1.2Term Multiple myeloma progression
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the preliminary efficacy of bb2121 in subjects with relapsed and refractory multiple myeloma (RRMM) and in subjects with high risk (HR) multiple myeloma (MM) having progressed within one year of initial treatment
    Evaluar la eficacia preliminar del bb2121 en pacientes con MMRR o con MM de AR con signos de progresión de la enfermedad en el año siguiente a la administración de un tratamiento inicial.
    E.2.2Secondary objectives of the trial
    - Evaluate the safety of bb2121 in subjects with RRMM and in subjects with HR MM having progressed within one year of initial treatment
    - Evaluate additional efficacy parameters of bb2121
    - Characterize the expansion and persistence of chimeric antigen receptor (CAR) + T cells, in the peripheral blood and bone marrow (by vector copy number [VCN])
    - Evaluate the development of an anti-CAR antibody response
    - Evaluate the percentage of subjects who attain minimal residual disease (MRD) negative status (by EuroFlow and next generation sequencing [NGS])
    - Evaluate changes in health-related quality of life (HRQoL)
    • Evaluar la seguridad del bb2121 en pacientes con MMRR y en pacientes con MM de AR que hayan empeorado en el año siguiente a la administración del tratamiento inicial
    • Evaluar parámetros de eficacia adicionales del bb2121
    • Caracterizar la expansión y la persistencia de linfocitos T con receptor de antígeno quimérico (CAR, chimeric antigen receptor) en sangre periférica y médula ósea en función del número de copias del vector (VCN, vector copy number)
    • Evaluar el desarrollo de una respuesta de anticuerpos anti-CAR
    • Evaluar el porcentaje de pacientes que presentan enfermedad mínima residual (EMR) negativa mediante EuroFlow y secuenciación de nueva generación (SNG)
    • Evaluar los cambios en la calidad de vida relacionada con la salud (HRQoL, Health Related Quality of Life)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF)
    2. Subject has measurable disease, defined as:
    • M-protein (serum protein electrophoresis [sPEP] or urine protein electrophoresis [uPEP]): sPEP ≥ 0.5 g/dL or uPEP ≥ 200 mg/24 hours and/or
    • Light chain MM without measurable disease in the serum or urine: Serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
    3. Subjects with one of the following cohort specific requirements:
    Cohort 1 RRMM subjects with ≥ 3 prior anti-myeloma treatment regimens:
    • Subject must have received at least 3 prior anti-myeloma treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen
    • Subject must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen
    • Subject must have received prior treatment with a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody
    • Subject has evidence of PD on or within 60 days of the most recent prior treatment regimen
    • Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen
    Cohort 2 HR and with 1 prior anti-myeloma treatment regimen:
    • Subject must have received only 1 prior anti-myeloma treatment regimen. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen
    • Subject must have the following HR factors:
    - R-ISS stage III
    AND
    - Early relapse defined as:
    - For subjects that have undergone transplant, PD < 12 months since date of first transplant
    - For subjects that have received only induction, PD < 12 months since date of last treatment regimen which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone
    4. Subject must have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
    5. Subject must have recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy
    6. Subject must have adequate vascular access for leukapheresis
    7. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
    8. Subject is willing and able to adhere to the study visit schedule and other protocol requirements as well as agrees to continued follow up for up to 15 years as mandated by the regulatory guidelines for gene therapy trials
    9. Female subjects of childbearing potential (FCBP) must:
    • Have a negative pregnancy test as verified by the Investigator, one negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test result at screening, prior to LD chemotherapy. This applies even if the subject practices true abstinence* from heterosexual contact
    • Either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective measures of contraception without interruption, from screening through at least 1 year following last bb2121 infusion. Contraception methods must include 1 highly effective and 1 additional effective (barrier) method of contraception from screening until at least 12 months following bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests
    • Agree to abstain from breastfeeding during study participation and for at least 1 year post-bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests
    10. Male subjects must:
    • Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing for at least 1 year post bb2121 infusion, even if he has undergone a successful vasectomy from screening until at least 1 year following last bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests
    • Must not donate sperm for at least 12 months following last bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests
    1. Sujetos ≥18 años en el momento de firmar el formulario de consentimiento informado (FCI).
    2. Sujetos que tengan enfermedad mensurable, definida como:
    • Proteínas M (electroforesis de proteínas séricas [EFPS] o electroforesis de proteínas urinarias [EFPU]): EFPS ≥0,5 g/dl o EFPU ≥200 mg/24 horas y/o
    • MM de cadenas ligeras sin enfermedad mensurable en suero u orina: cadenas ligeras libres de inmunoglobulinas en suero ≥10 mg/dl y alteración del cociente de cadenas ligeras libres κ/λ de inmunoglobulinas en suero.
    3. Sujetos que cumplan uno de los siguientes requisitos específicos para su cohorte:
    Sujetos de la cohorte 1 con MMRR que se hayan sometido a ≥3 tratamientos previos para el mieloma:
    • Sujetos que hayan recibido al menos 3 tratamientos previos para el mieloma. Nota: la inducción con o sin trasplante de progenitores hematopoyéticos y con o sin tratamiento de mantenimiento se considera un único tratamiento.
    • Sujetos que hayan recibido al menos dos ciclos consecutivos en cada tratamiento, salvo que la PE haya sido la mejor respuesta.
    • Sujetos que hayan recibido tratamiento previo con un inhibidor del proteasoma, un inmunomodulador y un anticuerpo anti-CD38.
    • Sujetos que hayan mostrado indicios de PE en los 60 días siguientes al tratamiento previo más reciente.
    • Sujetos que hayan respondido (respuesta mínima [RM] o mejor) al menos a 1 tratamiento previo.
    Cohorte 2 de AR y con 1 tratamiento previo para el mieloma:
    • Sujetos que hayan recibido solo 1 tratamiento previo para el mieloma. Nota: la inducción con o sin trasplante de progenitores hematopoyéticos y con o sin tratamiento de mantenimiento se considera un único tratamiento.
    • Sujetos que presenten los siguientes factores de AR:
    - Estadio III del R-ISS
    Y
    - Recidiva precoz, definida como:
    - En el caso de los sujetos que se hayan sometido a un trasplante, PE <12 meses desde la fecha del primer trasplante.
    - En el caso de los sujetos que solo hayan recibido inducción, PE <12 meses desde la fecha del último tratamiento, que debe contener, como mínimo, un inhibidor del proteasoma, un inmunomodulador y dexametasona.
    4. Sujetos que tengan un estado funcional ≤1 en la escala del Eastern Cooperative Oncology Group (ECOG).
    5. Sujetos que muestren recuperación a grado 1 o al nivel basal respecto a cualquier toxicidad no hematológica debida a tratamientos previos, excluida la alopecia y la neuropatía de grado 2.
    6. Sujetos que tengan un acceso vascular adecuado para realizar la leucocitaféresis.
    7. Sujetos que comprendan y firmen voluntariamente un FCI antes de que se realicen evaluaciones o procedimientos relacionados con el estudio.
    8. Sujetos que tengan disposición y capacidad para cumplir el calendario de visitas del estudio y otros requisitos establecidos en el protocolo y accedan a someterse a un seguimiento continuado durante un periodo de hasta 15 años tal como exigen las directrices reguladoras para ensayos con terapias génicas.
    9. Mujeres en edad fértil (MEF) que:
    • Hayan obtenido un resultado negativo en una prueba de embarazo verificada por el investigador, un resultado negativo en la prueba de embarazo de la gonadotropina coriónica humana (β-hCG) en suero durante la selección, antes de recibir la quimioterapia de DL. Esto será aplicable incluso aunque la participante practique una abstinencia real* de relaciones sexuales heterosexuales.
    • Se comprometan a una abstinencia real* de relaciones sexuales heterosexuales, o bien acepten y tengan capacidad para usar métodos anticonceptivos eficaces de forma ininterrumpida desde la selección hasta un año después de la última perfusión de bb2121. Los métodos anticonceptivos deben incluir un método muy eficaz y un método anticonceptivo eficaz adicional (de barrera) desde la selección hasta al menos 12 meses después de la perfusión de bb2121 y hasta que ya no se detecten linfocitos T con CAR mediante qPCR en dos pruebas consecutivas.
    • Acepten abstenerse de amamantar durante la participación en el estudio, hasta que haya transcurrido al menos 1 año desde la última perfusión bb2121 y hasta que ya no se detecten linfocitos T con CAR mediante qPCR en dos pruebas consecutivas.
    10. Sujetos varones que:
    • Practiquen una abstinencia real* o acepten usar un preservativo durante las relaciones sexuales con mujeres embarazadas o en edad fértil hasta que haya transcurrido al menos 1 año desde la última perfusión bb2121, incluso aunque se hayan sometido con éxito a una vasectomía, desde la selección hasta al menos 1 año después de la última perfusión de bb2121 y hasta que ya no se detecten linfocitos T con CAR mediante qPCR en dos pruebas consecutivas.
    • No donen esperma durante al menos los 12 meses siguientes a la última perfusión de bb2121 y hasta que ya no se detecten linfocitos T con CAR mediante qPCR en dos pruebas consecutivas.
    E.4Principal exclusion criteria
    1. Subject used any investigational agents within 28 days of leukapheresis
    2. Subject received any of the following within the last 14 days of leukapheresis:
    a. Plasmapheresis
    b. Major surgery (as defined by the investigator)
    c. Radiation therapy other than local therapy for myeloma associated bone lesions
    d. Use of any systemic anti-myeloma drug therapy
    3. Subject with known CNS involvement with myeloma
    4. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation
    5. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis. (Note: Only if subject experienced Grade 4 neurotoxicity following bb2121 treatment is this exclusion criteria applicable before retreatment with bb2121 (Cohort 1)
    6. Subject with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis
    7. Subject has nonsecretory MM
    8. Subject has any of the following laboratory abnormalities:
    a. Absolute neutrophil count (ANC) < 1,000/μL
    b. Platelet count < 50,000 mm3 in the absence of transfusion support (platelet transfusion within 7 days of screening)
    c. Hemoglobin < 8 g/dL (< 4.9 mmol/L) (it is not permissible to transfuse a subject to reach this level)
    d. Serum Creatinine Clearance (CrCl) < 45 mL/min
    e. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
    f. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN)
    g. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome
    h. International ratio (INR) or partial thromboplastin time (PTT) > 1.5 × ULN, or history of Grade ≥ 2 hemorrhage within 30 days, or subject requires ongoing treatment with chronic, therapeutic dosing of anticoagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors)
    9. Echocardiogram (ECHO) or multi-gated acquisition (MUGA) with left ventricular ejection fraction < 45%
    10. Subject with a history of Class III or IV congestive heart failure (CHF) or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months prior to starting study treatment
    11. Inadequate pulmonary function defined as oxygen saturation (Sa02) < 92 % on room air
    12. Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are allowed
    13. Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy
    14. Subject has received ASCT within 12 weeks prior to leukapheresis
    15. Subject has history of primary immunodeficiency
    16. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C
    17. Subject has uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment
    18. Subject with prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following noninvasive malignancies:
    a. Basal cell carcinoma of the skin
    b. Squamous cell carcinoma of the skin
    c. Carcinoma in situ of the cervix
    d. Carcinoma in situ of the breast
    e. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative
    19. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during participation in the study
    20. Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab
    21. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
    22. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. This includes systemic fungal, bacterial, viral, or other infection that is uncontrolled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial treatment) or requiring IV antimicrobials for management.
    23. Subject has any condition that confounds the ability to interpret data from the study.
    1Suj q hayan tomado algún fármaco en investigación 28 días previos a la leucocitaféresis2Sujq se hayan sometido a alguno de los siguientes procedimientos 14 días previos a la leucocitaféresis aPlasmaféresisbCirugía mayor (definida por el investigador)cRadioterapia u otro tto local para lesiones óseas asociadas al mielomadUso de algún tto farmacológico sistémico para el mieloma
    3Suj con afectación conocida del SNC y mieloma4Suj con indicios clínicos de leucostasis pulmonar y coagulación intravascular diseminada5Antecedentes o presencia de enfermedad del SNC clínicamente relevante como, epilepsia,convulsiones,paresia,afasia,apoplejía,hemorragia subaracnoidea u otra hemorragia del SNC,lesiones cerebrales graves,demencia,enfermedad de Parkinson, enfermedad cerebelosa,síndrome psiquiátrico de causa orgánica o psicosis.(Nota: este criterio de exclusión solo se aplica antes de la repetición del tto con bb2121 si el suj presenta neurotoxicidad grado 4 tras el tto con bb2121 (cohorte 1).6Suj con presencia activa o antecedentes de leucemia de células plasmáticas, macroglobulinemia de Waldenström, síndrome POEMS (polineuropatía,organomegalia, endocrinopatía,proteínas monoclonales y cambios en la piel) o amiloidosis clínicamente significativa.7Suj con MM no secretor.8Suj con alguna de las alteraciones analíticas: aRecuento absoluto de neutrófilos (RAN) <1000/μl.bPlaquetas <50 000 mm3 en ausencia de apoyo con transfusión (transfusión plaquetaria durante los 7 días previos a la selección).cHemoglobina <8 g/dl (<4,9 mmol/l) (nopermitido realizar una transfusión a un suj para q alcance dicha concentración).dAclaramiento creatinina (AcCr) en suero <45 ml/min.
    eCalcio sérico corregido >13,5 mg/dl (>3,4 mmol/l).fAspartato-aminotransferasa (AST) o alanina-aminotransferasa (ALT) en suero >2,5 veces el límite superior de la normalidad (LSN).
    gBilirrubina total en suero >1,5 veces el LSN o >3,0 mg/dl en el caso de los suj con síndrome de Gilbert documentado.hCociente internacional normalizado (CIN) o tiempo de tromboplastina parcial (TTP) >1,5 × LSN, o antecedentes de hemorragia de grado ≥2 en un plazo de 30 días, o suj q requieran tto continuo con la adm crónica y terapéutica de anticoagulantes (p. ej., warfarina, heparina de bajo peso molecular o inhibidores del factor Xa)9Ecocardiograma (ECO) o ventriculografía nuclear (MUGA) con fracción de eyección del ventrículo izquierdo <45 %.
    10Antecedentes insuficiencia cardíaca congestiva (ICC) clase III o IV o cardiomiopatía no isquémica grave, angina inestable o mal controlada, infarto de miocardio o arritmia ventricular durante los 6 meses anteriores al inicio del tto del estudio.11Función pulmonar inadecuada, definida como saturación de oxígeno (Sa02) <92 % en aire ambiente.12Tto en curso con inmunodepresores crónicos (p. ej., ciclosporina o corticoesteroides sistémicos en cualquier dosis).Se permite el tto intermitente con corticoesteroides tópicos, inhalados o intranasales.13Antecedentes de alotrasplante de progenitores hematopoyéticos o tto con cualquier terapia génica para el cáncer o terapia celular en investigación para el cáncer o terapia dirigida contra BCMA14Suj q se hayan sometido a un ATPH en las 12 semanas previas a la leucocitaféresis.15Suj con antecedentes de inmunodeficiencia primaria.16Suj con el virus de la inmunodeficiencia humana (VIH-1), hepatitis B activa o crónica o hepatitis A o C activa.17Suj con infección sistémica fúngica, bacteriana o vírica o infección de otro tipo (incluida la tuberculosis) sin controlar, a pesar de haber recibido un tto adecuado con antibióticos o de otro tipo.18Suj con antecedentes de otras neoplasias malignas, además del MM, salvo q el sujeto lleve ≥5 años sin la enfermedad, excepto en el caso de las siguientes neoplasias malignas no invasivas:aCarcinoma basocelular cutáneo.bCarcinoma epidermoide cutáneo.cCarcinoma cervicouterino localizado.dCarcinoma de mama localizado.eHallazgo histológico de cáncer de próstata (T1a o T1b usando el stma de estadificación clínica TNM [por tumor, ganglios y metástasis]) o cáncer de próstata q se pueda curar.19Mujeres embarazadas o lactantes, o q tengan previsto quedarse embarazadas mientras participan en el estudio.20Suj con hipersensibilidad conocida a cualquier componente del producto bb2121, ciclofosfamida, fludarabina y/o tocilizumab.21Suj con cualquier afección médica, alteración analítica o trastorno psiquiátrico significativos q les impida participar en el estudio.22Suj con cualquier afección, incluida la presencia d alteraciones analíticas, q suponga para ellos un riesgo inaceptable si participan en el estudio, por ej, infecciones sistémicas fúngicas, bacterianas o víricas o infecciones d otro tipo sin controlar ( signos/síntomas persistentes relacionados con la infección, qno mejoran a pesar de la adm de un tto antimicrobiano adecuado) o qprecisen un tto con antimicrobianos intravenosos.23Suj con cualquier afección qafecte a la capacidad para interpretar los datos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    - Overall response rate (ORR) (Cohort 1)
    - Complete response (CR) rate (Cohort 2)
    - Tasa de respuesta global (TRG) en la cohorte 1
    - Tasa de respuesta completa (RC) en la cohorte 2
    E.5.1.1Timepoint(s) of evaluation of this end point
    Starting from M2, response will be assessed at every month for the first 6 months then every 3 months for a minimum of 24 months or until progressive disease (PD) up to 5 years after the last subject has received the first bb2121 infusion, whichever is longer
    A partir del M2, se evaluará la respuesta todos los meses durante los 6 primeros meses y, a continuación, cada 3 meses durante un mínimo de 24 meses o hasta la progresión de la enfermedad (PE) hasta un máximo de 5 años desde que el último sujeto haya recibido la primera perfusión de b2121, el plazo que sea mayor.
    E.5.2Secondary end point(s)
    - Complete response (CR) rate (Cohort 1)
    - Overall response rate (ORR) (Cohort 2)
    - Time to response (TTR)
    - Duration of response (DoR)
    - Progression-free survival (PFS)
    - Time to progression (TTP)
    - Overall survival (OS)
    - Safety
    - Pharmacokinetics
    - Immunogenicity
    - Minimal Residual Disease (MRD)
    - Health-related Quality of Life (HRQoL)
    Tasa de respuesta completa (RC) (cohorte 1)
    - Tasa de respuesta global (TRG) (cohorte 2)
    - Tiempo hasta la respuesta (TR)
    - Duración de la respuesta (DR)
    - Supervivencia sin progresión (SSP)
    - Tiempo hasta la progresión (TP)
    - Supervivencia global (SG)
    - Seguridad
    - Farmacocinética
    - Inmunogenia
    - Enfermedad mínima residual (EMR)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Starting from M2, response will be assessed at every month for the first 6 months then every 3 months for a minimum of 24 months or until progressive disease (PD) up to 5 years after the last subject has received the first bb2121 infusion, whichever is longer
    At the time of documented PD, all subjects will be followed for survival every 3 months until the end of the trial (up to 5 years after the last subject received first bb2121 infusion in the respective cohort)
    Safety: continuously
    - PK: D3, D5, D8, D10, D12, D15, D18, D22, M2, M7, M10, M13, M16, M19, M22, M25, M31, every 6 months
    - immunogenicity: D25, M2, M3, M4, M7, M10, M19, M31, every 12 months
    - MRD: M2, M4, M7, M13, M19, M25, every 12 months
    - HRQoL: D1, M2-M7, M10, M13, M16, M19, M22, M25, M28, M31, M34, every 3 months
    Desde M2, se evaluará respuesta todos los meses durante los 6 primeros y a continuación cada 3 durante un mín de 24 o hasta progresión d la enfermedad (PE) hasta un máx de 5 años dsd q el último suj haya recibido la 1ª perfusión b2121, el plazo q sea mayor. Cdo se verifique PE, los suj se someterán a seguimiento de supervivencia cada 3m hasta final de ensayo (hasta un máx d 5 años desde q el último suj haya recibido la primera perfusión de b2121 en la cohorte correspondiente).
    Seguridad: de forma continuada.FC: D3, D5, D8, D10, D12, D15, D18, D22, M2, M7, M10, M13, M16, M19, M22, M25, M31, cada 6 meses.Inmunogenia: D25, M2, M3, M4, M7, M10, M19, M31, cada 12 meses.EMR: M2, M4, M7, M13, M19, M25, cada 12 meses.HRQoL: D1, M2-M7, M10, M13, M16, M19, M22, M25, M28, M31, M34, cada 3 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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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 Yes
    E.8.1.7.1Other trial design description
    2 cohorts
    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 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 EEA6
    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
    France
    Germany
    Italy
    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 Trial is defined as either the date of the last visit of the last subject to complete the post treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.
    El final del ensayo se define como la fecha de la última visita del último sujeto en finalizar el seguimiento postratamiento, o bien como la fecha de recepción del último dato del último sujeto necesario para el análisis principal, secundario y/o exploratorio, de la forma previamente especificada en el protocolo, lo que suceda más tarde.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months3
    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: 73
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 49
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 122
    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)
    Because this protocol involves gene transfer, long-term follow-up for lentiviral vector safety will be followed under a separate LTFU protocol (GC-LTFU-001), for up to 15 years after the last bb2121 CAR T cell infusion.
    All subjects who have completed survival follow-up period specified in this protocol, or are withdrawn from this study will be enrolled into the GC-LTFU-001study.
    Este protocolo implica la transferencia de genes, por lo que se realizará un seguimiento a largo plazo de la seguridad del vector lentivírico en un protocolo de SGLP diferente (GC-LTFU-001), durante un periodo de hasta 15 años tras la última perfusión de linfocitos T con CAR.
    Todos los sujetos que hayan finalizado el periodo de seguimiento de la supervivencia especificado en este protocolo o que sean retirados de este estudio se incorporarán al estudio GC-LTFU-001.
    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 Decision2018-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-01
    P. End of Trial
    P.End of Trial StatusRestarted
    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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