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    Summary
    EudraCT Number:2018-000264-28
    Sponsor's Protocol Code Number:bb2121-MM-002
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-10-17
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-000264-28
    A.3Full title of the trial
    A Phase 2, Multi-Cohort, Open-Label, Multi-center 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)
    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.
    A.4.1Sponsor's protocol code numberbb2121-MM-002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCelgene Corporation
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1888260 1599
    B.5.5Fax number+1913266 0394
    B.5.6E-mailClinicalTrialDisclosure@celgene.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/17/1863
    D.3 Description of the IMP
    D.3.1Product nameAutologous T lymphocyte-enriched population of cells transduced with a lentiviral vector
    D.3.2Product code bb2121 (ide-cel)
    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.3.9.3Other descriptive namebb2121 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
    E.1.1.1Medical condition in easily understood language
    Cancer of the bone marrow that recurs or is resistant to treatment
    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 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
    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 kinetics-pharmacokinetics [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)
    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 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

    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
    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.
    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)
    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
    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) negative rate
    - Health-related Quality of Life (HRQoL)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Starting M2, response will be assessed 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
    - 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
    Refer to Table 3 in protocol for details for each Cohort
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    2 cohorts
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the 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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Germany
    Italy
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The End of Trial is defined as either the date of the last visit of the last subject to complete the post treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.
    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: 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.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-11-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-18
    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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