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    EudraCT Number:2018-000264-28
    Sponsor's Protocol Code Number:bb2121-MM-002
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-10
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    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)
    Étude de phase II multicentrique, multi-cohortes, en ouvert, visant à déterminer l’efficacité et la sécurité du bb2121 chez des patients atteints d’un myélome multiple récidivant ou réfractaire et chez des patients atteints de myélome multiple à haut risque ayant évolué dans l’année suivant le traitement initial (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.
    Une étude visant à évaluer l'efficacité et la sécurité de bb2121 chez les personnes atteintes de myélome qui ne répondent pas au traitement ou qui ont eu un myélome après un traitement.
    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
    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. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product Yes
    D. 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
    Myélome multiple récidivant et réfractaire et myélome multiple à haut risque ayant progressé dans l'année suivant le traitement initial
    E.1.1.1Medical condition in easily understood language
    Cancer of the bone marrow that recurs or is resistant to treatment
    Cancer de la moelle osseuse récidivant ou résistant au traitement
    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
    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)
    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
    - 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.Le patient a au moins 18 ans au moment de la signature du FCE
    2.Le patient a une maladie mesurable, se définissant comme suit
    •Protéine M (électrophorèse des protéines sériques [EPS] ou électrophorèse des protéines urinaires [EPU]) : EPS ≥ 0,5 g/dl ou EPU ≥ 200 mg/24 heures ou
    •MM à chaînes légères sans maladie mesurable dans le sérum ou les urines : Chaînes légères libres sériques d’immunoglobines ≥ 10 mg/dl et ratio anormal de chaînes légères libres sériques kappa sur lambda d’immunoglobines
    3.Patients présentant l’une des conditions requises suivantes de la cohorte
    Patients atteints de MMRR de la cohorte 1 ayant déjà suivi au moins 3 protocoles de traitement anti-myélome
    •Le patient doit avoir déjà suivi au moins 3 protocoles de traitement anti-myélome.Rq: un traitement d’induction avec ou sans greffe de cellules souches hématopoïétiques et avec ou sans traitement d’entretien est considéré comme un seul protocole
    •Le patient doit avoir suivi au moins deux cycles consécutifs de traitement pour chaque protocole, sauf si une PM a été la meilleure réponse au protocole
    •Le patient doit avoir reçu un traitement antérieur par un inhibiteur du protéasome, un immunomodulateur ou un anticorps anti-CD38
    •Le patient peut justifier d’une PM dans les 60 jours suivant le protocole de traitement antérieur le plus récent
    •Le patient affiche une réponse (RM ou MR) à au moins 1 protocole de traitement antérieur
    Patients à HR de la cohorte 2 ayant déjà suivi au moins 1 protocole de traitement anti-myélome
    •Le patient doit avoir suivi un seul protocole de traitement anti-myélome antérieur. Remarque : un traitement d’induction avec ou sans greffe de cellules souches hématopoïétiques et avec ou sans traitement d’entretien est considéré comme un seul protocole.
    •Le patient doit présenter les facteurs HR suivants :
    R-ISS stade III
    ET Récidive précoce définie comme :
    Pour les patients ayant reçu une greffe, PM < 12 mois depuis la date de la première greffe
    Pour des patients ayant reçu uniquement le traitement d’induction, PM < 12 mois depuis la date du dernier protocole de traitement devant contenir au moins un inhibiteur du protéasome, un immunomodulateur et de la dexaméthasone
    4.Le patient doit afficher un indice de performance Eastern Cooperative Oncology Group (ECOG) ≤ 1
    5.Le patient doit être ramené au grade 1 ou à la valeur à l’inclusion de toute toxicité non hématologique liée à des traitements antérieurs, en excluant l’alopécie et la neuropathie de grade 2
    6.Le patient doit présenter un accès vasculaire adéquat pour la leucaphérèse
    7.Le patient doit comprendre et signer volontairement un FCE avant la réalisation de toute évaluation ou procédure liée à l’étude
    8.Le patient est prêt à adhérer au programme des visites de l’étude et aux autres conditions stipulées au protocole, et est en mesure de le faire, et il consent à une poursuite du suivi sur 15 ans au plus, comme le prévoient les directives réglementaires pour les essais de thérapie génique.
    9.Les femmes en âge de procréer doivent remplir les critères suivants :
    •présenter un test de grossesse négatif vérifié par l’investigateur
    •S’engager à respecter une abstinence véritable de rapports hétérosexuels ou accepter d’utiliser et être capable d’utiliser correctement des méthodes de contraception efficaces sans interruption, depuis la sélection jusqu’à un an après la dernière perfusion de bb2121.
    •Accepter de s’abstenir d’allaiter pendant la participation à l’étude et pendant au moins un an après la perfusion bb2121 et jusqu’à la disparition totale des lymphocytes T CAR dans deux dosages consécutifs par PCR quantitative.
    10.Les patients masculins doivent :
    •Pratiquer l’abstinence véritable2 ou convenir d’utiliser un préservatif pendant les rapports sexuels avec une femme enceinte ou une femme en âge de procréer pendant au moins un an après la perfusion de bb2121, même s’ils ont subi une vasectomie réussie entre la sélection et au moins un an après la dernière perfusion de bb2121, et jusqu’à disparition totale des lymphocytes T CAR dans deux dosages consécutifs par PCR quantitative.
    •S’abstenir de faire don de leur sperme pendant au moins 12 mois après la dernière perfusion de bb2121 et jusqu’à la disparition totale des lymphocytes T CAR dans deux dosages consécutifs par PCR quantitative
    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.
    Si un patient remplit l’un des critères suivants, il ne pourra pas participer à l’étude :
    1.Prise de médicaments expérimentaux dans les 28 jours précédant la leucaphérèse
    2.Le patient a reçu l’un des traitements suivants au cours des 14 jours précédant la leucaphérèse :
    b.Intervention chirurgicale majeure (selon l’investigateur)
    c.Radiothérapie, sauf radiothérapie locale des lésions osseuses provoquées par le myélome
    d.Pharmacothérapie systémique du myélome
    3.Le myélome du patient atteint son système nerveux central.
    4.Signes cliniques de leucostase pulmonaire et de coagulation intravasculaire disséminée
    5.Antécédents ou présence d’une pathologie du SNC cliniquement pertinente, notamment : épilepsie, convulsion, parésie, aphasie, AVC, hémorragies méningées ou autre hémorragie du SNC, lésions cérébrales importantes, démence, maladie de Parkinson, maladie cérébelleuse, syndrome cérébral organique ou psychose. (Remarque : ces critères d’exclusion avant un nouveau traitement au bb2121 (cohorte 1) ne sont applicables que si le patient a présenté une neurotoxicité de grade 4 après un traitement au bb2121.
    6.Antécédents ou présence de leucémie plasmocytaire, macroglobulinémie de Waldenström, syndrome POEMS (polyneuropathie, organomégalie, endocrinopathie, gammapathie monoclonale et anomalies cutanées) ou amyloïdose cliniquement significative.
    7.MM non sécrétant
    8.Anomalies biologiques suivantes :
    a.Numération absolue des neutrophiles (NAN) < 1 000/μl
    b.Numération plaquettaire < 50 000 mm3 en l’absence de transfusion (transfusion de plaquettes dans les sept jours précédant la sélection)
    c.Hémoglobine < 8 g/dl (< 4,9 mmol/l) (aucune transfusion n’est autorisée pour atteindre ce taux)
    d.Clairance de la créatinine sérique (ClCr) < 45 ml/min
    e.Calcium sérique corrigé > 13,5 mg/dl (> 3,4 mmol/l)
    f.Aspartate aminotransférase (ASAT) ou alanine aminotransférase (ALAT) sérique > 2,5 x limite supérieure de la normale (LSN)
    g.Bilirubine sérique totale > 1,5 × LSN ou > 3,0 mg/dl pour des patients présentant un syndrome de Gilbert établi
    h.Taux normalisé international (INR) ou temps de céphaline activé (TCA) > 1,5 × LSN ou antécédents d’hémorragie de grade ≥ 2 dans les 30 jours, ou le patient requiert la poursuite d’un traitement anticoagulant à une posologie thérapeutique régulière (par ex., warfarine, héparine à faible poids moléculaire, inhibiteurs du facteur Xa)
    9.Échocardiogramme (ÉCHO) ou ventriculographie isotopique à l’équilibre (MUGA) avec fraction d’éjection du ventricule gauche < 45 %
    10.Antécédents d’insuffisance cardiaque congestive de classe III ou IV ou de cardiomyopathie non ischémique sévère, angine de poitrine instable ou mal contrôlée, infarctus du myocarde ou arythmie ventriculaire au cours des six mois précédant le début du traitement de l’étude
    11.Fonction pulmonaire insuffisante définie par une saturation en oxygène (SaO2) < 92 % à l’air ambiant
    12.Traitement en cours par immunosuppresseurs chroniques (par ex., cyclosporine ou corticoïdes systémiques à une dose quelconque). Les corticoïdes par voie topique, inhalée ou intranasale sont autorisés en traitement intermittent.
    13.Antécédents d’allogreffe de cellules souches hématopoïétiques, de traitement anticancéreux à base de thérapie génique, de thérapie cellulaire expérimentale anticancéreuse ou de thérapie ciblant l’antigène de maturation des lymphocytes B (BCMA).
    14.Greffe autologue de cellules souches au cours des 12 semaines précédant la leucaphérèse
    15.Antécédents d’immunodéficience primaire
    16.Infection par le virus de l’immunodéficience humaine (VIH-1), hépatite B chronique ou active, ou hépatite A ou C active
    17.Infection systémique fongique, bactérienne, virale ou autre infection (y compris la tuberculose) non jugulée en dépit d’un traitement antibiotique ou d’un autre traitement approprié
    18.Antécédents de tumeurs malignes, autres que le MM, à moins d’une rémission complète de cinq ans ou plus et à l’exception des cancers non invasifs suivants :
    a.Carcinome basocellulaire,
    b.Carcinome épidermoïde cutané,
    c.Carcinome in situ du col de l’utérus,
    d.Carcinome in situ du sein.
    e.Découverte histologique fortuite d’un cancer de la prostate (de stade T1a ou T1b selon la classification TNM [tumeur, envahissement ganglionnaire, métastases]) ou cancer de la prostate curable.
    19.S’il s’agit d’une patiente : grossesse, allaitement ou projet de grossesse pendant la participation à l’étude
    20.Hypersensibilité connue à l’un des composants du bb2121, au cyclophosphamide, à la fludarabine ou au tocilizumab
    21.Toute condition médicale, anomalie d’analyses biologiques ou maladie psychiatrique qui empêcherait le patient de participer à l’étude
    22.Toute affection dont la présence d’anomalies aux analyses biologiques, qui exposerait le patient à un risque inacceptable s’il participait à l’étude
    23.Toute affection qui altérerait l’interprétation des données de l’étude
    E.5 End points
    E.5.1Primary end point(s)
    - Overall response rate (ORR) (Cohort 1)
    - Complete response (CR) rate (Cohort 2)
    - Taux de réponse global (TRG) (Cohorte 1)
    - Taux de réponse complète (CR) (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
    À partir de M2, la réponse sera évaluée tous les mois pendant les 6 premiers mois puis tous les 3 mois pendant au moins 24 mois ou jusqu'à la progression de la maladie (PD) jusqu'à 5 ans après que le dernier patient ait reçu la première perfusion bb2121, selon le plus long
    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)
    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
    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. 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. 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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    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
    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.
    La fin de l'essai est définie soit comme la date de la dernière visite du dernier patient pour compléter le suivi post-traitement, soit la date de réception du dernier point de données du dernier patient requis pour le s analyses primaire, secondaire et / ou exploratoire, telle que spécifiée dans le protocole, quelle que soit la date la plus tardive.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months9
    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 No
    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.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-01-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-17
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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