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    Summary
    EudraCT Number:2019-001264-30
    Sponsor's Protocol Code Number:CARAMBA-1
    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:2022-07-11
    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 number2019-001264-30
    A.3Full title of the trial
    A phase I/IIa clinical trial to assess feasibility, safety and antitumor activity of autologous SLAMF7 CAR-T cells in multiple myeloma
    Ensayo clínico fase I/IIa para evaluar la viabilidad, la seguridad y la actividad antitumoral de linfocitos autólogos CAR-T SLAMF7 en mieloma múltiple
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A first-in-human clinical study to assess feasibility, safety and antitumor activity of genetically modified T-cells in multiple myeloma
    Primer estudio clínico en humanos para evaluar la viabilidad, la seguridad y la actividad antitumoral de células T genéticamente modificadas en mieloma múltiple
    A.4.1Sponsor's protocol code numberCARAMBA-1
    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 SponsorUniversitätsklinikum Würzburg
    B.1.3.4CountryGermany
    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 supportUniversity Hospital of Würzburg
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportEU Framework Programme "Horizon 2020"
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSERMES PLANIFICACION S.L
    B.5.2Functional name of contact pointSTART UP UNIT
    B.5.3 Address:
    B.5.3.1Street AddressCalle Rufino González, 14-2º D
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28037
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491327 50 25
    B.5.5Fax number+3491754 27 21
    B.5.6E-mailstart-up@sermescro.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/3/17/1833
    D.3 Description of the IMP
    D.3.1Product nameSLAMF7 CAR-T
    D.3.4Pharmaceutical form Suspension for injection
    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 INNINN not available yet
    D.3.9.3Other descriptive nameSLAMF7 CAR-T
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.01 to 1
    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 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
    Multiple myeloma (MM)
    Mieloma múltiple (MM)
    E.1.1.1Medical condition in easily understood language
    Plasma cell cancer
    Cáncer de células plasmáticas
    E.1.1.2Therapeutic area Body processes [G] - Physiological processes [G07]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1.) Phase I: Safety determination of the treatment with SLAMF7 CAR-T;
    2.) Phase I: Determination of the MTD and the recommended phase IIa dose of SLAMF7 CAR-T
    3.) Phase IIa: Safety determination of the treatment with SLAMF7 CAR-T;
    4.) Phase IIa: Evaluation of the efficacy, defined as overall response rate (ORR) of SLAMF7 CAR-T in patients with MM
    1) Fase I : Determinar la seguridad del tratamiento con CAR-T SLAMF7
    2) Fase I: Determinar la DMT y la dosis recomendada para la fase IIa de CAR-T SLAMF7
    3) Fase IIa: Determinar la seguridad del tratamiento con CAR-T SLAMF7
    4) Fase IIa : Evaluar la eficacia, definida como tasa de respuesta global (TRG) de CAR-T SLAMF7 en pacientes con MM
    E.2.2Secondary objectives of the trial
    1.) Evaluation of the complete response (CR) of SLAMF7 CAR-T in patients with MM
    2.) Determination of the feasibility to ex vivo manufacture of autologous SLAMF7 CAR-T and to administer to patients with MM;
    3.) Determination of the expansion and duration of in vivo persistence of adoptively transferred SLAMF7 CAR- T cells in peripheral blood, bone marrow and tumor tissue;
    4.) To determine if the adoptive transfer of SLAMF7 CAR-T has an anti-myeloma effect;
    5.) Determination of the SLAMF7 CAR-T cells impact on patient’s overall survival (OS);
    6.) To determine if the adoptive transfer of SLAMF7 CAR-T affects the quality of life

    Further exploratory objectives, please refer to the exploratory end points listed below
    1) Evaluar la respuesta completa (RC) de CAR-T SLAMF7 en pacientes con MM
    2) Determinar la viabilidad de fabricar ex vivo CAR-T SLAMF7 autólogos y administrar a pacientes con MM
    3) Determinar la expansión y duración de la persistencia in vivo de células CAR-T SLAMF7 transferidas de forma adoptiva en sangre periférica, médula ósea y tejido tumoral
    4) Determinar si la transferencia adoptiva de CAR-T SLAMF7 tiene efecto anti-mieloma
    5) Determinar el impacto de las células CAR-T SLAMF7 en la supervivencia global (SG) de los pacientes
    6) Determinar si la transferencia adoptiva de CAR-T SLAMF7 afecta la calidad de vida relacionada con la salud (CVRS)


    Otros objetivos exploratorios, por favor consulte las variables exploratorias enumeradas a continuación
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent form.
    2. Patient is ≥18 years of age.
    3. Patient is willing and able to adhere to the protocol requirements.
    4. Patient with diagnosis of MM who has been treated with at least 2 prior lines of treatment, including at least one cycle of high-dose chemotherapy with autologous hematopoietic stem cell transplantation if the patient was eligible, and exposure to an immunomodulatory imide drug (e.g. lenalidomide and/or pomalidomide), a proteasome inhibitor, and an anti-CD38 antibody.
    (Note: Induction therapy, up to 2 cycles of high-dose chemotherapy with autologous hematopoietic stem cell transplantation, and subsequent consolidation and/or maintenance therapy are considered one line of treatment).
    5. At least one of the following subcriteria must be measured in the patient:
    - Serum M-protein greater or equal to 0.5 g/dL
    - Urine M-protein greater or equal to 200 mg/24 h
    - Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal
    - A biopsy-proven evaluable plasmacytoma
    - Bone marrow plasma cells >10% of total bone marrow cells (>30% if bone marrow plasma cells are the only marker of measurable disease)
    6. Patients previously treated with an anti-SLAMF7 antibody are eligible.
    7. Karnofsky performance status ≥60%. If patient has a Karnofsky performance status <60% (e.g. after a spinal cord injury) but is judged to be medically fit by the investigator, patient is eligible.
    8. Female patients of childbearing potential must:
    a) have a negative pregnancy test (blood) at screening.
    b) 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 1 year following the IMP infusion. A highly effective method of contraception or birth control (failure rate less than 1% per year when used consistently and correctly) must be practiced. The patient should be informed of the potential risks associated with becoming pregnant while enrolled in this clinical trial. Reliable methods for this trial are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence or vasectomized sexual partner. Abstinence is only accepted as true abstinence: when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal] are not acceptable methods of contraception.) Postmenopausal (no menses for at least 1 year without alternative medical cause) or surgically sterile female patients (tubal ligation, hysterectomy or bilateral oophorectomy) may be enrolled.
    c) Agree to abstain from breast feeding during the study participation and for 1 year after the IMP infusion.
    9. Male patients must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 1 year after IMP infusion, even if he has undergone a successful vasectomy.
    1. Consentimiento informado firmado.
    2. El paciente tiene ≥18 años de edad.
    3. El paciente está dispuesto y es capaz de cumplir con los requisitos del protocolo.
    4. Paciente con diagnóstico de MM que ha sido tratado con al menos 2 líneas de tratamiento previas, incluyendo al menos un ciclo de alta dosis de quimioterapia con transplante autólogo de células madre hematopoyéticas si el paciente fuera elegible, y exposición a un medicamento inmumodulador (IMID) (por ejemplo: lenalidomida y/o pomalidomida), un inhibidor del proteasoma y un anticuerpo monoclonal anti-CD38.
    (Nota: La terapia de inducción, hasta 2 ciclos de quimioterapia en dosis altas seguido de trasplante autólogo de progenitores hematopoyéticos, y la posterior terapia de consolidación y/o mantenimiento, se consideran una línea de tratamiento).
    5. Al menos uno de los siguientes subcriterios debe medirse en el paciente:
    - Proteína M sérica mayor o igual a 0,5 g/dL
    - Proteína M urinaria mayor o igual a 200 mg/24 h
    - Análisis de cadenas ligeras libres séricas (FLC): FLC involucrada mayor o igual a 10 mg/dL (100 mg/L), siempre que la relación de FLC sérica sea anormal
    - Plasmocitoma evaluable confirmado por biopsia
    - Células plasmáticas en médula ósea >10% del total de células en la médula ósea (>30% si las células plasmáticas de la médula ósea son el único marcador de enfermedad medible)
    6. Los pacientes tratados previamente con un anticuerpo anti-SLAMF7 son elegibles.
    7. Escala Karnofsky ≥60%. Si el paciente tiene un estado funcional de Karnofsky <60% (por ejemplo, después de una lesión de la médula espinal) pero el investigador lo considera como médicamente apto, el paciente es elegible.
    8. Las mujeres en edad fértil deberán:
    a) tener una prueba de embarazo negativa (sangre) en el cribado
    b) además, comprometerse con abstinencia verdadera de contacto heterosexual; o bien aceptar el uso, y ser capaz de cumplir, con medidas efectivas de anticoncepción sin interrupción, desde el cribado hasta 1 año después de la perfusión del producto médico en investigación(PMI). Se debe utilizar un método anticonceptivo o de control de natalidad (tasa de fallo inferior a 1% anual cuando se utiliza de manera consistente y correcta). Se debe informar al paciente de los riesgos potenciales asociados con quedar embarazada durante su participación dentro del ensayo clínico. Para este ensayo son métodos fiables: anticoncepción hormonal combinada (que contenga estrógeno y progestágeno) asociada con inhibición de la ovulación (oral, intravaginal, transdérmica), anticoncepción hormonal solo progestágeno asociada con inhibición de la ovulación (oral, inyectable, implantable), dispositivo intrauterino, sistema de liberación de hormonas intrauterinas, ligadura de trompas bilateral, abstinencia sexual o pareja sexual vasectomizada. La abstinencia solo se acepta como verdadera cuando está en línea con el estilo de vida preferido y habitual del paciente. (La abstinencia periódica [por ejemplo, calendario, ovulación, métodos sintotérmicos, método post-ovulación y método de retiro] no son anticonceptivos aceptables). Se pueden incluir pacientes posmenopáusicas (sin menstruación durante al menos 1 año sin causa médica alternativa) o mujeres quirúrgicamente estériles (ligadura de trompas tubáricas bilateral, histerectomía u ooforectomía bilateral).
    c) abstención de lactancia durante la participación en el estudio y durante 1 año después de la perfusión del PMI.
    9. Los pacientes varones deben practicar abstinencia verdadera o aceptar el empleo de preservativo durante el contacto sexual con una mujer embarazada o una mujer en edad fértil durante al menos 1 año después de la perfusión del PMI, incluso si se ha sometido a una vasectomía exitosa.
    E.4Principal exclusion criteria
    1. Patient has undergone a prior allogeneic stem cell transplant with either standard or reduced intensity conditioning ≤12 months prior to leukapheresis.
    2. Patient has undergone a prior allogeneic stem cell transplant with either standard or reduced intensity conditioning >12 months, and suffers on chronic Graft-versus-Host Disease and/or is on systemic immune-suppressants.
    3. Patient with diagnosis of MM
    a. in first relapse following an autologous stem cell transplantation or
    b. in second relapse that subsequently achieves a complete response
    that is considered being a candidate for an allogeneic stem cell transplantation, unless the patient explicitly denies undergoing an allogeneic stem cell transplantation
    4. Patient has received anti-CD38 and/or anti-SLAMF7 antibodies ≤8 weeks prior to leukapheresis.
    5. Ongoing treatment with immune-suppressants (e.g. cyclosporine or systemic steroids at any dose).
    (Note: Physiologic steroid replacement therapy, and topical steroids are permitted.)
    6. Echocardiogram with left ventricular ejection fraction <45%.
    7. Inadequate renal function defined by creatinine clearance (CrCl) ≤45 mL/min using Cockcroft-Gault equation.
    8. Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) and total bilirubin >1.5 x ULN (unless due to Gilbert’s syndrome and direct bilirubin is ≤1.5 x ULN; unless due to intrahepatic myeloma lesions as demonstrated by MRI or positron emission tomography [PET]/computed tomography [CT] not older than 4 weeks prior to screening).
    9. International ratio (INR) or partial thromboplastin time (PTT) >1.5 x ULN, unless on a stable dose of anti-coagulant.
    10. Evidence of human immunodeficiency virus (HIV) infection.
    11. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV), excluding
    - Patients who are HBsAg negative and HBV viral DNA negative
    - Patients who had hepatitis B but have received an antiviral treatment and show non-detectable viral DNA for 6 months
    - Patients who are seropositive because of hepatitis B virus vaccine
    - Patients with known HBV infection but undetectable HBV viral load and on anti-viral therapy to prevent HBV reactivation.
    12. Seropositive for and with active viral infection with hepatitis C virus (HCV), excluding
    - Patients who had hepatitis C but had received an antiviral treatment and show no detectable HCV viral RNA for 6 months.
    13. Seropositive for syphilis on treponema pallidum hemagglutination test, excluding
    - Patients with negative treponema pallidum antibody absorption test result
    14. Patients with active infection or other serious medical or psychiatric disorder on investigators decision.
    15. Pregnant or lactating women.
    16. Current or previous (within 30 days of enrollment) treatment with another IMP.
    17. Known abuse of alcohol, drugs, or medicinal products.
    18. Employees of the sponsor, or employees or relatives of the investigator.
    1. El paciente se ha sometido a un trasplante alogénico de progenitores hematopoyéticos con un acondicionamiento de intensidad estándar o reducida ≤12 meses antes de la leucoaféresis.
    2. El paciente se ha sometido a un trasplante alogénico de progenitores hematopoyéticos con un acondicionamiento de intensidad estándar o reducida > 12 meses, y presenta enfermedad de injerto contra receptor crónica y/o recibe inmunosupresores sistémicos.
    3. Paciente con diagnóstico de MM
    a. En una primera recaída después de un transplante autólogo de células madre o
    b. En una segunda recaída que posteriormente logra una respuesta completa
    que está considerado ser un candidato para un transplante de células madre alogénicas, a menos que el paciente niegue explícitamente someterse a un transplante de células madre alogénicas
    4. El paciente ha recibido anticuerpos anti-CD38 y/o anti-SLAMF7, ≤ 8 semanas antes de la leucoaféresis.
    5. Tratamiento continuo con inmunosupresores (por ejemplo: ciclosporina o esteroides sistémicos a cualquier dosis).
    (Nota: Se permiten esteroides de terapia de reemplazo hormonal fisiológica y esteroides tópicos).
    6. Ecocardiograma con fracción de eyección ventricular izquierda <45%.
    7. Función renal inadecuada definida por el aclaramiento de creatinina ≤ 45 mL/min utilizando la ecuación de Cockcroft-Gault.
    8. Función hepática inadecuada definida por aspartato aminotransferasa (AST) y/o alanina aminotransferasa (ALT) >2,5 veces el límite superior de la normalidad (LSN) y bilirrubina total >1,5 veces el LSN (a menos que presente síndrome de Gilbert y la bilirrubina directa sea ≤1.5 veces el LSN; o lesiones intrahepáticas secundarias al mieloma y que sean demostradas por resonancia magnética (RM) o tomografía por emisión de positrones [PET]/ tomografía computarizada [TC] no más de 4 semanas antes del cribado).
    9. Cociente internacional normalizado (INR) o tiempo de tromboplastina parcial (TTP) >1,5 veces el LSN, a menos que reciba una dosis estable de anticoagulante.
    10. Evidencia de infección por el virus de inmunodeficiencia humana (VIH).
    11. Seropositivo para y con evidencia de infección viral activa por el virus de la hepatitis B (VHB), excluyendo:
    - Pacientes negativos para el antígeno de superficie de la hepatitis B y con ADN del VHB negativo.
    - Pacientes que han tenido hepatitis B pero han recibido tratamiento antiviral y el ADN viral es indetectable durante 6 meses.
    - Pacientes seropositivos debido a la vacuna contra el virus de la hepatitis B.
    - Pacientes con infección conocida por VHB pero con carga viral del VHB indetectable y bajo terapia antiviral para prevenir la reactivación del VHB.
    12. Seropositivo para y con infección viral activa por el virus de la hepatitis C (VHC), exluyendo:
    - Pacientes que tuvieron hepatitis C pero que habían recibido un tratamiento antiviral y no muestran ARN viral detectable del VHC durante 6 meses.
    13. Seropositivo para sífilis en la prueba de hemaglutinación del Treponema pallidum, excluyendo:
    - Pacientes con prueba de absorción de anticuerpos contra Treponema pallidum negativa.
    14. Pacientes con infección activa u otro trastorno médico o psiquiátrico grave por decisión de los investigadores.
    15. Mujeres embarazadas o lactando.
    16. Tratamiento actual o previo (dentro de los 30 días de la inclusión) con otro PMI.
    17. Abuso conocido de alcohol, drogas o medicamentos.
    18. Empleados del promotor, o empleados o parientes del investigador.
    E.5 End points
    E.5.1Primary end point(s)
    1.) Phase I: Type, frequency, and severity of adverse events (AEs), including serious adverse events (SAEs), cytokine release syndrome (CRS), and neurotoxicity (i.e. immune effector cell-associated neurotoxicity syndrome [ICANS])
    2.) Phase I: MTD of SLAMF7 CAR-T that can be administered in phase IIa will be assessed at the end of phase I
    3.) Phase IIa: Type, frequency, and severity AEs, including SAEs, CRS, and neurotoxicity (i.e. ICANS)
    4.) Phase IIa: Percentage of patients who achieved partial response (PR) or better using the IMWG Uniform Response Criteria for Multiple Myeloma at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24 after SLAMF7 CAR-T infusion
    1) Fase I : Tipo, frecuencia y gravedad de los efectos adversos (EA), incluidos los EA graves (EAG), el síndrome de liberación de citocinas (SLC) y la neurotoxicidad (síndrome de neurotoxicidad asociado a células inmunes efectoras [ICANS])
    2) Fase I: se evaluara al final de la Fase I la DMT de CAR-T SLAMF7 que se administrará en la fase IIa
    3) Fase IIa: Tipo, frecuencia y gravedad de los EA, incluyendo EAG, SLC y neurotoxicidad (ICANS)
    4) Fase IIa : Porcentaje de pacientes que lograron respuesta parcial (RC) o mejor, utilizando los criterios de respuesta del IMWG para MM en los meses 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, y 24 después de la perfusión CAR-T SLAMF7
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.) D0, 4 hours after infusion, D1 to D28, W5, W6, W7, W8, W10, W12, M4 to M12, M15, M18, M24
    2.) End of phase I
    3.) D0, 4 hours after infusion, D1 to D28, W5, W6, W7, W8, W10, W12, M4 to M12, M15, M18, M24
    4.) M1 to M6, M9, M12, M15, M18, M21, M24
    1.) D0, 4 horas después de la perfusión, D1 a D28, W5, W6, W7, W8, W10, W12, M4 a M12, M15, M18, M24
    2.) Fin de la fase I
    3.) D0, 4 horas después de la perfusión, D1 a D28, W5, W6, W7, W8, W10, W12, M4 a M12, M15, M18, M24
    4.) M1 a M6, M9, M12, M15, M18, M21, M24
    E.5.2Secondary end point(s)
    1.) Phase IIa: Percentage of patients who achieved CR or better using the IMWG Uniform Response Criteria for Multiple Myeloma at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24 after SLAMF7 CAR-T infusion
    2.) Phase I and IIa: Percentage of myeloma patients enrolled into the trial who receive ex vivo expanded autologous SLAMF7 CAR-T within the 48h shelf-life of the product
    3.) Phase I and IIa: Maximum peak in SLAMF7 CAR-T (Cmax), time to peak of SLAMF7 CAR-T (Tmax), area under the curve of CAR-T CD4+ and CD8+ cells (AUC), including maximum expansion and duration of persistence of SLAMF7 CAR-T cells at Baseline, Days 0 (4 hours), 1, 3, 7, 10, 14, 21, 28, Week 6, 8, 12, Months 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24
    4.) Phase I and IIa:
    a) Time between first SLAMF7 CAR-T infusion and first documentation of response at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24;
    b) Time between first response and disease progression PD or death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
    c) Time between SLAMF7 CAR-T infusion and first documentation of PD or death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
    d) Phase I and IIa: Proportion of minimal residual disease (MRD) evaluable patients that are MRD negative (defined at a minimum of 1 in 105 nucleated cells) using flow cytometry at Months 1, 3, 6, 12, 24
    5.) Phase I and IIa: Time between SLAMF7 CAR-T infusion and time of death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
    6.) Patient-reported outcomes as measured by EORTC-QLQ-C30/-MY20 at Screening, Baseline, Months 6, 12, 24

    Exploratory end points:
    1.) Immunophenotype of SLAMF7 CAR-T and endogenous immune cells in the peripheral blood and bone marrow at Baseline, Months 1, 3, 6, 12, 24
    2.) Cytokine/chemokine levels in the blood at Baseline, Days 0 (4 hours), 1, 3, 7, 10, 14, 21, 28, Week 6, 8, 12, Months 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24
    3.) Humoral or cellular immune response against the SLAMF7 CAR-T at Months 1, 3, 6, 12, 24
    4.) Changes in gene expression profile or clonal composition at Baseline, Months 1, 3, 6, 12, 24
    5.) Expression of SLAMF7 on myeloma cells and endogenous immune cells after SLAMF7 CAR-T therapy at Baseline, Months 1, 3, 6, 12, 24
    6.) Kinetic and frequency of SLAMF7 CAR-T after activation of the EGFRt depletion marker in peripheral blood (on Days 0, 1, 3, 7, 10, 14, 21, 28 after administering the first dose of anti-EGFR antibody) and in bone marrow (on Day 28 after administering the first dose of anti-EGFRt antibody)
    7.) Number of inpatient intensive care unit (ICU) days, inpatient non-ICU days, outpatient visits and concomitant medications at Months 6, 12, 24
    1) Fase IIa : Porcentaje de pacientes que lograron RC o mejor, utilizando los criterios de respuesta del IMWG para MM en los meses 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, y 24 después de la perfusión CAR-T SLAMF7
    2) Fase I y IIa: Porcentaje de pacientes con mieloma incluidos en el ensayo que reciben CAR-T SLAMF7 autólogos expandidos ex vivo dentro de las 48 horas de vida útil del producto
    3) Fase I y IIa: Pico máximo de CAR-T SLAMF7 (Cmax), tiempo hasta el pico de CAR-T SLAMF7 (Tmax), área bajo la curva de células CAR-T CD4+ y CD8+ (AUC), incluyendo la expansion máxima y la duración de la persistencia de las células CAR-T SLAMF7 basal, días 0 (4 horas), 1, 3, 7, 10, 14, 21, 28, semanas 6, 8, 12, meses 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21 y 24
    4) Fase I y IIa :
    a) Tiempo entre la primera perfusión de CAR-T SLAMF7 y la primera documentación de respuesta en los meses 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 y 24
    b) Tiempo entre la primera respuesta y la progresión de la enfermedad (PE) o muerte en los meses 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 y 24
    c) Tiempo entre la perfusión de CAR-T SLAMF7 y la primera documentación de PE o muerte en los meses 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 y 24
    d) Fase I y IIa :Proporción de pacientes evaluables de enfermedad minima residual (EMR) que son EMR negativos (definido en un mínimo de 1 de cada 105 células nucleadas) utilizando citometría de flujo en los meses 1, 3, 6, 12 y 24
    5) Fase I y IIa: Tiempo entre la perfusión de CAR-T SLAMF7 y la muerte en los meses 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 y 24
    6) CVRS notificado por el paciente medido por EORTC-QLQ-C30/-MY20 en el cribado, basal y meses 6, 12, 24

    Variables exploratorias
    1) Inmunofenotipo de CAR-T SLAMF7 y células inmunes endógenas en la sangre periférica y la médula ósea al inicio y meses 1, 3, 6, 12, 24
    2) Niveles de citocinas / quimiocinas en la sangre al inicio, día 0 (4 horas), 1, 3, 7, 10, 14, 21, 28, semana 6, 8, 12, meses 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24
    3) Respuesta inmune humoral o celular contra el CAR-T SLAMF7 en los meses 1, 3, 6, 12, 24
    4) Cambio, con respecto al basal, en inmunofenotipo, perfil de expresión génica y composición clonal en meses 1, 3, 6, 12, 24
    5) Expresión de SLAMF7 en células de mieloma y células inmunitarias endógenas después de la terapia CAR-T SLAMF7 en los meses 1, 3, 6, 12, 24
    6) Cinética y frecuencia de CAR-T SLAMF7 después de la activación del marcador de agotamiento EGFRt en sangre periférica (en los días 0, 1, 3, 7, 10, 14, 21, 28 después de administrar la primera dosis del anticuerpo anti-EGFR) y en la médula ósea (el día 28 después de administrar la primera dosis del anticuerpo anti-EGFRt)
    7) Número de días en la Unidad de Cuidados Intensivos (UCI), días de hospitalización no UCI, visitas ambulatorias y medicamentos concomitantes a los meses 6, 12, 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.) M1 to M6, M9, M12, M15, M18, M21, M24
    2.) D0
    3.) Baseline (BL) (D-8), D0 (4 hours), D1, D3, D7, D10, D14, D21, D28, W6, W8, W12, M4 to M12, M15, M18, M21, M24
    4.) M1 to M6, M9, M12, M15, M18, M21, M24
    5.) M1 to M6, M9, M12, M15, M18, M21, M24
    6.) Screening, BL, M1 to M6, M9, M12, M15, M18, M21, M24
    7.) M1, M3, M6, M12, M24
    8.) M1 to M6, M9, M12, M15, M18, M21, M24
    9.) M6, M12, M24

    Exploratory:
    1.) BL, M1, M3, M6, M12, M24
    2.) BL, D0 (4 hours), D1, D3, D7, D10, D14, D21, D28, W6, W8, W12, M4 to M12, M15, M18, M21, M24
    3.) M1, M3, M6, M12, M24
    4.) BL, M1, M3, M6, M12, M24
    5.) BL, M1, M3, M6, M12, M24
    Read the rest in protocol
    1.) M1 a M6, M9, M12, M15, M18, M21, M24
    2.) D0
    3.) Línea de base (BL) (D-8), D0 (4 horas), D1, D3, D7, D10, D14, D21, D28, W6, W8, W12, M4 a M12, M15, M18, M21, M24
    4.) M1 a M6, M9, M12, M15, M18, M21, M24
    5.) M1 a M6, M9, M12, M15, M18, M21, M24
    6.) Cribado, BL, M1 a M6, M9, M12, M15, M18, M21, M24
    7.) M1, M3, M6, M12, M24
    8.) M1 a M6, M9, M12, M15, M18, M21, M24
    9.) M6, M12, M24
    Exploratorio:
    1.) BL, M1, M3, M6, M12, M24
    2.) BL, D0 (4 horas), D1, D3, D7, D10, D14, D21, D28, W6, W8, W12, M4 a M12, M15, M18, M21, M24
    3.) M1, M3, M6, M12, M24
    4.) BL, M1, M3, M6, M12, M24
    5.) BL, M1, M3, M6, M12, M24
    Leer el resto en el protocolo
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy 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 Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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.8.3 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 EEA4
    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 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
    LSLV
    Última visita último sujeto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    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: 25
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 13
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 38
    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)
    When their trial participation has ended, patients will receive standard medical care according to their individual needs.
    Cuando finalice su participación en el ensayo, los pacientes recibirán atención médica estándar de acuerdo con sus necesidades individuales.
    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 Decision2020-07-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-03
    P. End of Trial
    P.End of Trial StatusOngoing
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