M32 M33 M34
Conditions
Interventions
Group 1: a prospective, open-label, single-dose, non-randomized, interventional basket trial
Single intravenous infusion of a freshly produced Advanced Therapy Medicinal Product (ATMP) of autologous a
Sponsors
Friedrich-Alexander-Universität Erlangen-Nürnberg, Medizinische Fakultät
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: General inclusion criteria • Subjects must understand and voluntarily sign an informed consent form including writ-ten consent for data protection, • Adults aged = 18 years at time of consent, • Adequate renal (eGFR > 30 ml/min/m2), liver (no Child Pugh C), heart (at worst NYHA III, EF > 30%) and pulmonary (FV and DLCO > 30%) function, • Male subjects unless surgically sterile, must agree to use two acceptable methods for contraception (e.g. spermicide and condom) during the trial and refrain from fathering a child starting from the time of signing the Informed Consent Form (ICF) until 12 months after dosing of the IMP, • Females of childbearing potential (FCBP) must have a negative urine pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl in-dex 4 U/l), anti-histone (+ or more), anti-nucleosome (+ or more) or anti-Sm antibodies (+ or more), • Active disease at screening, defined as = 1 organ system with a British Isles Lupus Assessment (BILAG) A score (severe disease activity) or = 2 organ systems with a BILAG B score (moderate disease activity) ([58]), • Insufficient response or intolerance/ contraindication to glucocorticoids and to at least 2 of the following treatments: hydroxychloroquine, mycophenolate mofetil, belimumab, methotrexate, rituximab, cyclophosphamide. Insufficient response is defined as having increased disease activity based on the definition explained in the previous bullet point. SSc subjects • Fulfilling the 2013 ACR/EULAR classification criteria of SSc ([14]), • Positivity (+ or more) for at least one SSc-specific parameter (Scl70, RNA polymerase, Th/To, RP11/12, U3RNP autoantibodies), • Signs for fast progression including (i) disease duration = 5 years (from onset of first non-Raynaud manifestation), (ii) mRSS score 10-35 at screening, (iii) elevated acute phase reactant levels (CRP = 6 mg/L, ESR = 28mm/h or platelet count = 330 G/L), (iii) mRSS increase = 3 units or involvement of one new body area or mRSS increase = 2 units in one body area or = 1 tendon friction rub over 6 months ([56]), • Insufficient response or intolerance/ contraindication to at least 2 of the following treat-ments: mycophenolate mofetil, azathioprine, nintedanib, methotrexate, rituximab. In-sufficient response is defined as having increased disease activity based on the defini-tion explained in the previous bullet point. DM/PM subjects • Fulfilling the 2017 ACR/EULAR classification criteria for probable or definite DM or PM ([65]), • Presence of active myositis in muscle biopsy or muscle MRI and/or signs of interstitial lung disease related to DM/PM, • Positivity (+ or more) for at least one myositis-specific antibody (aminoacyl tRNA syn-thetases, Mi2, MDA5, SAE, SRP, ARS, HMGCR, MJ, TIF1gamma), • Muscle weakness as define by MMT 0.25, at least one muscle enzyme > 1.3 times upper limit of normal, VAS global extra muscular activity = 2cm, • Insufficient response or into
Exclusion criteria
Exclusion criteria: • Clinically suitability for a less burdensome and/or approved therapeutic approach, as judged by the investigator, • ANC < 1.000/mm3, ALC < 500/mm3 or hemoglobin < 8g/dl, absolute CD3+ T cell count < 100/µl, • Uncontrolled severe concomitant disease, such as cancer (except basal or squamous cell skin cancer) and diabetes mellitus, • Severely impaired renal (eGFR = 30 ml/min/m2), liver (Child Pugh C), heart (NYHA IV, EF = 30%) and pulmonary (FV and DLCO = 30%) function, • Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study, • Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR T cell therapy), • History of bone marrow/ hematopoietic stem cell or solid organ transplantation, • Any concomitant severe active infection, e.g. HIV, hepatitis B or C, SARS-CoV 2 (COVID 19), or active tuberculosis as defined by a positive Quantiferon TB-test. If presence of latent tuberculosis is established then treatment according to local guidelines must have been initiated prior to enrollment, • Diagnosis of severe neuropsychiatric SLE, inclusion body myositis or limited SSc, • Pregnant or lactating females, • Females who are intending to conceive during the study, • Known hypersensitivity to any drug components, • Malignancy in the last 5 years before screening, • Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis, • Subjects who are younger than 18 years or are incapable to understand the aim, importance and consequences of the study and to give legal informed consent, • Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the Investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results, • Subjects who possibly are dependent on the Sponsor, the Principal Investigator or Investigator (e.g. family members).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence and grading of severity (graded 0-4) of Cytokine Release Syndrome (CRS) and of CAR T cell Associated Neurotoxicity Syndrome (ICANS) within the first 4 weeks after ATMP administration. | — |
Secondary
| Measure | Time frame |
|---|---|
| Clinical efficacy • Overall Response Rate (ORR) at week 24 measured by specific disease ac-tivity composite indexes, each of them validated for the specific disease: - SLE: Fulfillment of DORIS remission criteria of SLE at week 24. - SSc: No progression of interstitial lung disease with worsening of FVC1 (>10%) or worsening of FVC1 (5-10%) plus increase in respiratory symptoms or worsening of FVC1 (5-10%) plus progression of high-res-olution computed tomography changes after 24 weeks. - DM: 2016 ACR/EULAR Moderate or Major Response. Cellular and humoral response • Duration of persistence of CAR T cells in the peripheral blood • Duration of B cell depletion in the peripheral blood • Levels of respective serum autoantibodies at week 24 including incidence of sero-conversion - SLE: ANA, anti-dsDNA, anti-nucleosomes, anti-Sm, anti-cardiolipin IgG, C3 C4 - SSc: ANA, anti-SCL70, anti-RNA polymerase III, anti-topoisomerase - DM: ANA, anti-Mi2, anti-Tif1, anti-MDA5, anti-Jo1, anti-NXP2 • Expansion of CAR T cells in the patient over time • Success of the manufacturing process by GMP certification of the product Additional endpoints • General: - Patient’s Global Assessment (PtGA) of disease activity (VAS 0-100mm) - Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm) - Health Assessment Questionnaire – Disease Index (HAQ-DI) - Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT Fa-tigue) • SLE: - British Isles Lupus Assessment Group (BILAG) index - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) • SSc: - modified Rodnan Skin Score (mRSS) • DM/PM: - Physician’s global assessment (PhGA) of extramuscular activity - Manual Muscle Testing (MMT) | — |
Countries
Germany
Contacts
Public ContactGeorg Schett
Universitätsklinikum Erlangen, Medizinische Klinik 3, Rheumatologie und Immunologie
Outcome results
None listed