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    Summary
    EudraCT Number:2022-001796-14
    Sponsor's Protocol Code Number:CYTB323G12101
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-11-03
    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 ConcernedFrance - ANSM
    A.2EudraCT number2022-001796-14
    A.3Full title of the trial
    An open-label, multi-center, phase 1/2 study to assess safety, efficacy and cellular kinetics of YTB323 in participants with severe, refractory autoimmune disorders.
    Etude de phase I/II, multicentrique, en ouvert, visant à évaluer la tolérance, l’efficacité et la cinétique cellulaire de l’YTB323 chez des patients atteints de maladies auto-immunes sévères réfractaires
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open-label study to assess safety, efficacy and cellular kinetics of YTB323 in severe, refractory autoimmune disorders.
    Etude en ouvert, visant à évaluer la tolérance, l’efficacité et la cinétique cellulaire de l’YTB323 dans le cadre de maladies auto-immunes sévères réfractaires
    A.4.1Sponsor's protocol code numberCYTB323G12101
    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 SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma S.A.S
    B.5.2Functional name of contact pointInformation&Communication Médicales
    B.5.3 Address:
    B.5.3.1Street Address8/10 rue Henry Sainte Claire Deville, CS 40150
    B.5.3.2Town/ cityRueil-Malmaison
    B.5.3.3Post code92563
    B.5.3.4CountryFrance
    B.5.4Telephone number+33 1 5547 6600
    B.5.5Fax number+33 1 5547 6100
    B.5.6E-mailicm.phfr@novartis.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code YTB323
    D.3.4Pharmaceutical form Dispersion 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 INNNot estabilished
    D.3.9.3Other descriptive nameYTB323
    D.3.9.4EV Substance CodeSUB221189
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number5000000
    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 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
    Systemic Lupus Erythematosus
    Lupus Nephritis
    Lupus érythémateux systémique,
    Néphropathie lupique
    E.1.1.1Medical condition in easily understood language
    Systemic Lupus Erythematosus
    Lupus Nephritis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10042945
    E.1.2Term Systemic lupus erythematosus
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess safety of YTB323 in participants with srSLE and other severe forms of autoimmune diseases
    Evaluer la tolérance de l’YTB323 chez des patients atteints de LESsr et d’autresformes sévères de maladies auto-immunes
    E.2.2Secondary objectives of the trial
    •To characterize the in vivo cellular kinetics (pharmacokinetics, PK) of YTB323 in peripheral blood by quantitative polymerase chain reaction (qPCR)
    •To characterize the incidence and prevalence of pre-existing and treatment induced immunogenicity (cellular and humoral) of YTB323
    •To evaluate feasibility of the manufacturing process in autoimmune disorders
    •Part A: To assess the effect of YTB323 on the following SLE disease activity scores
    •Part A: To evaluate effect of YTB323 for srSLE participants who also have active lupus nephritis
    •Caractériser la cinétique cellulaire in vivo (pharmacocinétique [PK]) de lYTB323 dans le sang périphérique par Polymerase Chain Reaction quantitative (PCRq)
    •Caractériser l’incidence et la prévalence d’une immunogénicité (cellulaire et humorale) préexistante et induite par l’YTB323
    •Evaluer la faisabilité du procédé de production du traitement dans le cadre de maladies auto-immunes
    •Partie A : évaluer l’effet de l’YTB323 sur les scores d’activité de la maladie spécifiques au LES
    •Partie A : évaluer l’effet de l’YTB323 chez des patients atteints de LESsr ayant une néphropathie lupique active
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent.
    - Adequate renal, hepatic, cardiac, hematological and pulmonary function.
    - Men and women with SLE, aged ≥18 years and ≤65 years at acreening, fulfilling the 2019 European League Against Rheumatism EULAR/ACR classification criteria for SLE.
    - Patient must be positive for at least one of the following autoantibodies at screening: antinuclear antibodies (ANA) at a titer of ≥1:80, or anti dsDNA (above the ULN); or anti-Sm (above the ULN).
    - Active (severe) disease as defined by SLEDAI-2K ≥8 (not including the SLEDAI-2K domains of lupus headache, cerebrovascular accident, organic brain syndrome*) and at least one of the following significant SLE related organ involvements:
    - Renal
    - Peri/myocarditis
    - Pleuritis or other lung involvement
    - Other types of serositis such as peritoneal
    - Vasculitis

    - Failure to respond (i.e. having high disease activitiy as defined in criterion above despite the following therapy) to two or more standard immunosuppressive therapies (including one of mycophenolate or cyclophosphamide), unless contraindicated or having experienced documented adverse events or intolerance related to such immunosuppresive drugs not allowing their further use, in combination with glucocorticoids and failure to respond to at least on biological agent (unless contraindicated, the patient deemed ineligible by the Investigator or not available in a country).
    -Signature du consentement éclairé
    -Fonction rénale, hépatique, cardiaque et pulmonaire, et bilan hématologique adéquats (voir définitions en section 5.1 du protocole)
    -Hommes et femmes, âgés de 18 à 65 ans à la visite de sélection, et qui remplissent les critères de classification EULAR/ACR 2019 du LES (EULAR pour European League Against Rheumatism)/ (ACR pour American College of Rheumatology)
    -Présence à la sélection d’au moins un des auto-anticorps suivants : anticorps antinucléaires (AAN) avec un titre ≥ 1/80 ou anti-ADN double brin (> limite supérieure à la normale [LSN]) ; anticorps anti-Sm (> LSN)
    -Présence d’une maladie active (sévère) définie par un score SLEDAI-2K ≥8 (sans prise en compte des domaines du SLEDAI-2K tels que les céphalées, les accidents vasculaires cérébraux et les atteintes cérébrales liés au lupus *), et d’au moins une des atteintes significatives d’organe liées au LES suivantes :
    -Atteinte rénale** : diagnostic histologique de néphropathie lupique proliférative de classe III ou IV selon la classification de l’International Society of Nephrology and the Renal Pathology Society (ISN/RPS) et de l’Organisation Mondiale de la Santé (OMS) dans les 2 ans précédant la sélection ;
    ET présence d’au moins l’un des paramètres suivants à la sélection :
    -RPCU sur les premières urines du matin compris entre 0,7 et 4 mg/mg (entre 79,1 et 452 mg/mmol) ; ou
    -Sédiment urinaire compatible avec une néphropathie lupique proliférative active, tel que la présence de cylindres cellulaires (granuleux ou érythrocytaires)
    -Péricardite/myocardite
    -Pleurite ou autre atteinte pulmonaire
    -Autres types de sérosité, tels qu’une péritonéale
    -Vascularite
    Remarques :
    *Les patients atteints de LES neuropsychiatriques peuvent être inclus s’ils remplissent tous les autres critères d’éligibilité et qu’ils présentent un score SLEDAI-2K ≥8 pour les autres domaines.
    **Au moins deux tiers des patients doivent être atteints de néphropathie lupique telle que définie plus haut (voir également en section 4.1.1 du protocole)
    -Absence de réponse (c.-à-d. activité élevée de la maladie [voir critère ci-dessus] malgré les traitements mentionnés ci-après) à au moins 2 traitements immunosuppresseurs standards (dont un traitement par mycophénolate ou cyclophosphamide), sauf en cas de contre-indication, d’effets indésirables ou d’intolérance documentés à ces traitements ne permettant pas une administration ultérieure, en association avec des glucocorticoïdes et d’ absence de réponse à au moins un agent biologique (sauf en cas de contre-indication, de non éligibilité du patient selon l’investigateur, ou d’indisponibilité dans le pays concerné)
    E.4Principal exclusion criteria
    - Clinically signficant active, opportunistic, chronic or recurrent infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, such as COVID-19 etc.) one month prior to or during screening.
    - Uncontrolled diabetes mellitus, lung diseases or any other illness that are not related to SLE that in the opinion of the Investigator would jeopardize the ability of the patient to tolerate lymphodepletion and CD19 CAR T cell therapy.
    - Prior history of malignancy except for localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgica therapy, such as head and neck cancer, or stage I breast cancer will be considered on an individual basis.
    - Any patients requiring medications probited by the protocol.
    - Any psychiatric condition or disability compliance with treatment or informed consent impossible.
    - Prior treatment with anti-CD19 therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR-T cell therapy).
    - History o bone marrow/hematopoietic stem cell or solid organ transplantation.
    - Female participants who are pregnant or breastfeeding or intending to conceive during the course of the study.
    - Women of childbearing potential, defined as all womoen physiologically capable of becoming pregnant, unless they are using a highly effective method of contraception starting from the time of enrollment to at least 12 months after the YTB323 infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests.
    - Sexually active males unwilling to use a condom during intercourse from the time enrollment for at least 12 months after YTB323 infusion and until CAR-T cells ar eno longer present by qPCR on two consecutive tests.
    - Any acute, severe lupus related flare during screening that needs immediate treatment and/or makes the immunosuppressive washout impossible; thus, makes the patient ineligibile for CD19 CAR-T therapy as judged by the Investigator, such as acute central nervous system (CNS) lupus (e.g. psychosis, epilespy) or catastrophic antiphospholipid syndrome.
    - Significant, likely irreversible organ damage related to SLE, e.g. end stage renal disease, where, in the opinion of the Investigator CD19 CAR-T cell therapy would be unlikely to benefit the patient.
    • Infection active, récurrente, chronique ou opportuniste cliniquement significative, confirmée par des signes cliniques, des examens d’imagerie ou des analyses biologiques (par ex. hémoculture, PCR pour ADN/ARN, tel que le COVID-19 etc...) dans le mois précédant ou pendant la sélection
    • Diabète sucré non contrôlé, maladies pulmonaires ou toute autre maladie non liée au LES, et qui risqueraient , selon l’avis de l’investigateur de compromettre la capacité du patient à tolérer la lymphodéplétion et le traitement par cellules CAR-T CD19
    • Antécédents de tumeur maligne, à l’exception d’un carcinome épidermoïde ou basocellulaire localisé. Une évaluation au cas par cas sera effectuée pour les patients atteints d’autres tumeurs malignes ayant été jugées guéries par chirurgie locale, telles qu’un cancer de la tête et du cou ou un cancer du sein de stade I
    • Tout patient nécessitant un traitement interdit par le protocole
    • Toute pathologie psychiatrique ou handicap qui empêcherait le patient de se conformer au traitement ou de donner son consentement éclairé
    • Traitement antérieur par anti-CD19, thérapie cellulaire T adoptive ou thérapie génique (par ex. thérapie cellulaire à base de cellules CAR-T)
    • Patients ayant reçu une greffe de moelle osseuse/cellules souches hématopoïétiques ou d’organes solides
    • Femmes enceintes ou qui allaitent, ou qui prévoient de concevoir au cours de l’étude
    • Les femmes en âge de procréer, c’est-à-dire toutes les femmes physiologiquement aptes à être enceintes, à moins qu’elles n’utilisent une méthode de contraception très efficace à partir de l’inclusion et jusqu’à au moins 12 mois après la perfusion de l’YTB323, et jusqu’à ce que les cellules CAR-T ne soient plus détectables par PCRq sur 2 tests consécutifs
    • Les hommes sexuellement actifs refusant d'utiliser un préservatif à partir de l’inclusion et pendant au moins 12 mois après la perfusion de l’YTB323, et jusqu’à ce que les cellules CAR-T ne soient plus détectables par PCRq sur de 2 tests consécutifs
    • Toute poussée sévère et aiguë liée au lupus au moment de la sélection, nécessitant un traitement immédiat et/ou rendant impossible le washout du traitement immunosuppresseur, ce qui rendrait le patient inéligible au traitement par cellules CAR-T CD19, selon l’avis de l’investigateur, tels qu’une atteinte du système nerveux central (par ex. psychose, épilepsie) ou un syndrome catastrophique des anti-phospholipides
    • Dommages significatifs d’organe , probablement irréversible, associée au LES (par ex. insuffisance rénale terminale) qui ne permettrait pas au patient de retirer un bénéfice du traitement par cellules CAR-T CD19 selon l’avis de l’investigateur.
    E.5 End points
    E.5.1Primary end point(s)
    •Number of participants with AEs and SAEs
    E.5.1.1Timepoint(s) of evaluation of this end point
    720 days
    E.5.2Secondary end point(s)
    •CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood.
    •Cellular and humoral responses to CAR transgene.
    •Number of patients infused with planned target dose.
    •SLEDAI-2K
    •BILAG-2004
    •Physician's global assessment
    •LLDAS
    •Remission (DORIS)
    •SRI-4
    •BICLA
    •MCR
    •Urinary protein creatinine ratio
    •Complete Renal Response
    E.5.2.1Timepoint(s) of evaluation of this end point
    720 days
    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 Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    New indication/patient population
    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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    United States
    France
    Spain
    Germany
    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 study (or last participant last visit - LPLV) is when all participants have completed at least Month 24 evaluation or were withdrawn prematurely.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    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: 12
    F.1.3Elderly (>=65 years) No
    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 8
    F.4.2.2In the whole clinical trial 12
    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)
    All participants who either complete or prematurely discontinue from the study will be asked to participate in a long term follow-up (LTFU, see Section 4.1 of Protocol) either within this study or a dedicated LTFU study. In the LTFU semiannual and/or annual evaluations will be performed up to 15 years from the date of infusion as recommended by health authority guidance for participants treated with gene therapies.
    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 Decision2023-03-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-06-14
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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