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    Summary
    EudraCT Number:2018-000264-28
    Sponsor's Protocol Code Number:bb2121-MM-002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-15
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-000264-28
    A.3Full title of the trial
    A Phase 2, Multicohort, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of bb2121 in Subjects with Relapsed and Refractory Multiple Myeloma and in Subjects With Clinical High-Risk Multiple Myeloma (KarMMa-2)
    Studio di fase 2, a coorti multiple, in aperto, multicentrico per valutare l’efficacia e la sicurezza di bb2121 in soggetti con Mieloma Multiplo recidivante e refrattario e in soggetti con Mieloma Multiplo ad alto rischio clinico (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.
    Uno studio per valutare l’efficacia e la sicurezza di bb2121 in persone affette da mieloma che non risponde dopo il trattamento o che sono state affette da mieloma che è ricomparso dopo un periodo di trattamento.
    A.3.2Name or abbreviated title of the trial where available
    n.a.
    n.a.
    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 Address86 Morris Avenue
    B.5.3.2Town/ citySummit
    B.5.3.3Post codeNJ 07901
    B.5.3.4CountryUnited States
    B.5.4Telephone number+19137096862
    B.5.5Fax number+19088974074
    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 namePopolazione di cellule autologhe arricchite con linfociti T trasdotte con un vettore lentivirale (id
    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 INNIdecabtagene vicleucel
    D.3.9.2Current sponsor codebb2121 (ide-cel)
    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 (RRMM), multiple myeloma (MM) with progression within 18 months of initial treatment, or MM with inadequate response post autologous stem cell transplant (ASCT) during initial treatment
    Mieloma multiplo recidivato e refrattario (RRMM), mieloma multiplo (MM) con progressione entro 18 mesi dal trattamento iniziale, o MM con risposta inadeguata post trapianto autologo di cellule staminali (ASCT) durante il trattamento iniziale
    E.1.1.1Medical condition in easily understood language
    Cancer of the bone marrow that recurs or is resistant to treatment
    Cancro del midollo osseo che si ripresenta o è resistente al trattamento
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    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
    The primary objective of the study is to evaluate the efficacy of bb2121
    L’obiettivo primario dello studio è valutare l’efficacia di bb2121
    E.2.2Secondary objectives of the trial
    • Evaluate the safety of bb2121
    • Evaluate additional efficacy parameters of bb2121
    • Characterize the expansion and persistence of chimeric antigen receptor (CAR) + T cells, in the peripheral blood (cellular kineticspharmacokinetics [PK])
    • 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/or next generation sequencing [NGS])
    • Evaluate changes in health-related quality of life (HRQoL)
    • Valutare la sicurezza di bb2121
    • Valutare ulteriori parametri di efficacia di bb2121
    • Caratterizzare l’espansione e la persistenza delle cellule T positive per il recettore chimerico per l’antigene (Chimeric Antigen Receptor, CAR) nel sangue periferico(cinetica cellulare-farmacocinetica [PK])
    • Valutare lo sviluppo di una risposta anticorpale anti-CAR
    • Valutare la percentuale di soggetti che raggiungono lo stato negativo di malattia residua minima (Minimal Residual Disease, MRD) (mediante EuroFlow e/o sequenziamento in parallelo [Next generation sequencing, NGS])
    • Valutare i cambiamenti nella qualità della vita associata alla salute (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 subjects 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:
    Early relapse defined as:
    ¿ Cohort 2a: PD < 18 months since date of start of initial therapy. Initial therapy must contain induction, ASCT (single or tandem) and LEN containing maintenance
    ¿ Cohort 2b: PD < 18 months since date of start of initial therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone
    ¿ Cohort 2c: Subject must have received minimum 3 cycles of induction therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone. Subjects must have had ASCT (single or tandem)
    AND
    < VGPR (excluding PD) at first assessment between 70 to 110 days after last ASCT, with initial therapy without consolidation and maintenance
    4. Subject must have Eastern Cooperative Oncology Group (ECOG) performance status = 1
    5. Subject must have recovery to Grade 1 or baseline of any nonhematologic 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

    For the complete list of Inclusion Criteria, please refer to section “4.2. Inclusion Criteria” of Protocol version Final of 19Jun2018.
    1. Il soggetto ha 18 anni o più al momento della sottoscrizione del modulo di consenso informato (Informed Consent Form, ICF)
    2. Il soggetto ha una patologia misurabile, definita come:
    • Proteina M [elettroforesi delle proteine sieriche [Serum Protein Electrophoresis, sPEP] o elettroforesi delle proteine urinarie (Urine Protein Electrophoresis, uPEP)]: sPEP = 0,5 g/dL o uPEP = 200 mg/24 ore e/o
    • MM a catena leggera senza patologia misurabile nel siero o nell’urina:
    Catene leggere libere dell'immunoglobulina sierica = 10 mg/dL e rapporto delle catene leggere libere lambda/kappa dell'immunoglobulina sierica anomalo
    3. Soggetti con uno dei seguenti requisiti specifici per coorte:
    Coorte 1: soggetti affetti da RRMM con = 3 precedenti regimi di trattamento anti-mieloma:
    • Il soggetto deve aver ricevuto almeno 3 regimi precedenti di trattamento anti-mieloma. Nota: l’induzione con o senza trapianto di cellule staminali emopoietiche e con o senza terapia di mantenimento è considerata un regime singolo
    • Il soggetto deve essere stato sottoposto ad almeno 2 cicli consecutivi di trattamento per ciascun regime, salvo se la PD era la migliore risposta al regime
    • Il soggetto deve aver ricevuto un trattamento precedente con un inibitore del proteasoma, un agente immunomodulatore e un anticorpo anti-CD38
    • Il soggetto ha evidenza di PD durante o entro 60 giorni dal precedente regime di trattamento più recente
    • Il soggetto ha ottenuto una risposta (Risposta Minima (Minimal Response, MR) o migliore) ad almeno 1 regime di trattamento precedente
    Coorte 2: soggetti con 1 regime di trattamento anti-mieloma precedente:
    • Il soggetto deve aver ricevuto soltanto 1 regime di trattamento anti-mieloma precedente. Nota: l’induzione con o senza trapianto di cellule staminali emopoietiche e con o senza terapia di mantenimento è considerata un regime singolo
    • Il soggetto deve avere i seguenti fattori di HR:
    Recidiva precoce definita come:
    · Coorte 2a: PD < 18 mesi dalla data di avvio della terapia iniziale. La terapia iniziale deve prevedere la fase di induzione, ASCT (singolo o doppio) e il mantenimento con LEN
    · Coorte 2b: PD < 18 mesi dalla data di avvio della terapia iniziale che deve includere almeno un inibitore del proteasoma, un agente immunomodulante e desametasone
    · Coorte 2c: I soggetti devono avere ricevuto almeno 3 cicli di terapia di induzione che deve includere almeno un inibitore del proteasoma, un agente immunomodulante e desametasone. I soggetti devono avere ricevuto un ASCT (singolo o doppio)
    E
    < VGPR (che esclude la PD) alla prima valutazione a 70-110 giorni dopo l’ultimo ASCT, con terapia iniziale senza consolidamento e mantenimento
    4. Il soggetto deve avere un punteggio per il Performance Status ECOG (Eastern Cooperative Oncology Group) = 1
    5. Il soggetto deve avere un recupero al Grado 1 o al basale di qualsiasi tossicità non ematologica dovuta a trattamenti precedenti, escluse alopecia e neuropatia di Grado 2
    6. Il soggetto deve avere un accesso vascolare adeguato per la leucaferesi
    7. Il soggetto deve comprendere e firmare volontariamente l'ICF prima che venga condotta qualsiasi valutazione/procedura relativa allo studio
    8. Il soggetto è disposto e in grado di aderire al programma di visite previste dallo studio e ad altri requisiti del protocollo oltre ad accettare il follow-up continuo per massimo 15 anni, come richiesto dalle linee guida regolatorie per gli studi clinici su terapie geniche

    Per l’elenco completo dei Criteri di Inclusione, si prega di fare riferimento alla sezione “4.2. Inclusion Criteria” del Protocollo versione Finale del 19Jun2018.
    E.4Principal exclusion criteria
    1. Subject used any investigational agents within 14 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 central nervous system (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.
    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

    For the complete list of Exclusion Criteria, please refer to section “4.2. Exclusion Criteria” of Protocol version Final of 19Jun2018.
    1. Il soggetto ha utilizzato qualsiasi agente sperimentale entro 14 giorni dalla leucaferesi
    2. Il soggetto è stato sottoposto a uno qualsiasi dei seguenti entro gli ultimi 14 giorni di leucaferesi:
    a. Plasmaferesi
    b. Intervento chirurgico importante (come definito dallo sperimentatore)
    c. Radioterapia diversa dalla terapia locale per lesioni ossee associate al mieloma
    d. Uso di qualsiasi terapia farmacologica anti-mieloma
    3. Soggetto con coinvolgimento noto del sistema nervoso centrale (SNC) con mieloma
    4. Il soggetto ha evidenze cliniche di leucostasi polmonare e coagulazione intravascolare disseminata
    5. Pregressi o presenza di patologia del SNC clinicamente rilevante come epilessia, spasmi, paresi, afasia, ictus, emorragia subaracnoidea o altro sanguinamento del SNC, lesioni cerebrali gravi, demenza, morbo di Parkinson, patologia cerebellare, sindrome cerebrale organica o psicosi.
    6. Soggetto con pregressi o patologia in corso di leucemia plasmacellulare, macroglobulinemia di Waldenstrom, sindrome di POEMS (polineuropatia, organomegalia, endocrinopatia, proteina monoclonale e cambiamenti della pelle) o amiloidosi clinicamente significativa
    7. Il soggetto è affetto da MM non secernente
    8. Il soggetto ha una qualsiasi delle seguenti anomalie di laboratorio:
    a. Conta assoluta dei neutrofili (ANC) < 1.000/µL
    b. Conta piastrinica < 50.000 mm3 in assenza di supporto di trasfusione (trasfusione piastrinica entro 7 giorni dallo screening)
    c. Emoglobina < 8 g/dL (< 4,9 mmol/L) (non è concesso eseguire la trasfusione a un soggetto per raggiungere questo livello)
    d. Clearance della creatinina sierica (CrCl) < 45 mL/min
    e. Calcio sierico corretto > 13,5 mg/dL (> 3,4 mmol/L)
    f. Aspartato amminotransferasi sierica (AST) o alanina amminotransferasi (ALT) > 2,5 × limite superiore alla norma (ULN)
    g. Bilirubina sierica totale > 1,5 × ULN o > 3,0 mg/dL per soggetti con sindrome di Gilbert documentata
    h. Rapporto internazionale (INR) o tempo parziale della tromboplastina (PTT) > 1,5 × ULN, o anamnesi di emorragia di Grado = 2 entro 30 giorni, o il soggetto richiede il trattamento continuo con un dosaggio terapeutico cronico di anticoagulanti (ad es. warfarin, eparina a basso peso molecolare, inibitori del Fattore Xa)
    9. Ecocardiogramma (ECHO) o acquisizione con gate multipli (MUGA) con frazione di eiezione ventricolare sinistra < 45%
    10. Soggetto con pregressi di insufficienza cardiaca congestizia (Congestive Heart Failure, CHF) di Classe III o IV o cardiomiopatia non ischemica grave, angina instabile o scarsamente controllata, infarto del miocardio o aritmia ventricolare entro i precedenti 6 mesi prima dell’inizio del trattamento dello studio
    11. Funzione polmonare inadeguata definita come saturazione dell’ossigeno (Sa02) < 92% all’aria ambiente
    12. Trattamento in corso con immunosoppressori cronici (ad es. ciclosporina o steroidi sistemici a qualsiasi dose). I corticosteroidi topici, inalati o intranasali intermittenti sono concessi
    13. Pregressi di trapianto di cellule staminali emopoietiche allogeneiche o di trattamento con qualsiasi sostanza terapeutica basata sulla terapia genica per il cancro o di terapia cellulare sperimentale per il cancro o di terapia mirata al BCMA
    14. Il soggetto ha ricevuto ASCT entro 12 settimane prima della leucaferesi
    15. Il soggetto ha pregressi di immunodeficienza primaria
    16. Il soggetto è positivo al virus dell’immunodeficienza umana (HIV-1), epatite B cronica o attiva o epatite A o C attiva

    Per l’elenco completo dei Criteri di Esclusione, si prega di fare riferimento alla sezione “4.3. Exclusion Criteria” del Protocollo versione Final del 19Jun2018.
    E.5 End points
    E.5.1Primary end point(s)
    - Overall response rate (ORR) (Cohort 1)
    - Complete response (CR) rate (Cohort 2a, b and c)
    - Tasso di risposta complessiva (Overall Response Rate, ORR) (Coorte 1)
    - Tasso di risposta completa (Complete Response, CR) (Coorte 2a, b e c)
    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 partire da M2, la risposta sarà valutata ogni mese per i primi 6 mesi, poi ogni 3 mesi per un minimo di 24 mesi o fino a progressione della malattia (PD) per massimo 5 anni dopo che l’ultimo soggetto avrà ricevuto la prima infusione di bb2121, a seconda di quale periodo sia il più lungo
    E.5.2Secondary end point(s)
    - Complete response (CR) rate (Cohort 1)
    - Overall response rate (ORR) (Cohort 2a, b and c)
    - Very good partial response (VGPR) rate (Cohort 2c)
    - 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)
    - Tasso di risposta completa (CR) (Coorte 1)
    - Tasso di risposta complessiva (ORR) (Coorte 2a, b e c)
    - Tasso di Risposta parziale molto buona (VGPR) (Coorte 2c)
    - Tempo alla risposta (Time-To-Response, TTR)
    - Durata della risposta (Duration of Response, DoR)
    - Sopravvivenza senza progressione (Progression-Free Survival, PFS)
    - Tempo alla progressione (Time-To-Progression, TTP)
    - Sopravvivenza complessiva (Overall Survival, OS)
    - Sicurezza
    - Farmacocinetica
    - Immunogenicità
    - Malattia minima residua (MRD)
    - Qualità della vita correlata alla salute (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 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, M3, M4, M7, M13, M19, M25, every 12 months
    - HRQoL: D1, M2-M7, M10, M13, M16, M19, M22, M25, M28, M31, M34, every 3 months
    - A partire da M2, la risp sarà valutata ogni mese per i primi 6mesi, poi ogni 3mesi per un min di 24mesi o fino a progress della malattia per max 5 anni dopo che l’ultimo sogg avrà ricevuto la prima infus di bb2121, a seconda di quale periodo sia più lungo
    - Al momento della PD documentata, tutti i sogg saranno seguiti per la sopravviv ogni 3 mesi fino alla fine della sperim (per max 5 anni dopo che l’ultimo sogg avrà ricevuto la prima infus di bb2121 nella rispettiva coorte)
    - Sicurezza: in modo continuo
    - PK: G3, G5, G8, G10, G12, G15, G18, G22, M2, M7, M10, M13, M16, M19, M22, M25, M31, ogni 6 mesi
    - Immunogen: G25, M2, M3, M4, M7, M10, M19, M31, ogni 12 mesi
    - MRD: M2, M3, M4, M7, M13, M19, M25, ogni 12 mesi
    - HRQoL: G1, M2-M7, M10, M13, M16, M19, M22, M25, M28, M31, M34, ogni 3 mesi
    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 No
    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 coorti
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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 Information not present in EudraCT
    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 States
    France
    Germany
    Italy
    Spain
    United Kingdom
    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.
    Si definisce "fine della sperimentazione" o la data dell’ultima visita dell’ultimo soggetto che ha completato il follow-up post-trattamento o la data di ricezione dell’ultimo punto dati dall’ultimo soggetto che è richiesto per l’analisi primaria, secondaria e/o esplorativa, come predefinito nel protocollo, a seconda di quale sia la data che si verifica più tardi.
    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 months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months3
    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: 108
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 73
    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 36
    F.4.2.2In the whole clinical trial 181
    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.
    Dato che questo protocollo prevede il trasferimento genico, il follow-up a lungo termine per la sicurezza del vettore lentivirale sarà seguito sotto un protocollo di LTFU separato (GC-LTFU-001), per massimo 15 anni dopo l’ultima infusione di cellule T CAR di bb2121.
    Tutti i soggetti che completeranno il periodo di follow-up per la sopravvivenza specificato in questo protocollo, o che verranno ritirati da questo studio saranno arruolati nello studio 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 Decision2019-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-16
    P. End of Trial
    P.End of Trial StatusOngoing
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