CAR-T cells in systemic B cell mediated autoimmune disease - CASTLE

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Miltenyi Biomedicine GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Skin and Connective Tissue Diseases [C17], Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

16 May 2023 → ongoing

Decision date (initial)

2024-08-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Miltenyi Biomedicine GmbH

External identifiers

EU CT number

2024-516819-24-00

EudraCT number

2022-001366-35

ClinicalTrials.gov

NCT06347718

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the safety and toxicity of MB-CART19.1 in patients with active B-driven autoimmune disease (Systemic Lupus erythematosus [SLE], systemic sclerosis [SSc] and idiopathic inflammatory myopathy [IIM]).

Secondary objectives 5

1. To assess the clinical efficacy of anti-CD19 CAR T cell therapy in subjects with active B-driven autoimmune disease (SLE, SSc and IIM).
2. To investigate the duration of B cell depletion after anti-CD19 CAR T cell administration.
3. To investigate the duration of CAR T cell persistence after anti-CD19 CAR T cell administration.
4. To investigate the changes in the levels of disease-associated serum autoantibodies.
5. To investigate the in vivo cellular kinetics of MB-CART19.1, immunogenicity and feasibility of the manufacturing process.

Conditions and MedDRA coding

Systemic Sclerosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Adults aged ≥ 18 years at time of consent
2. SSC subjects: Fulfilling the 2013 ACR/EULAR classification criteria of SSc
3. SSC subjects: Positivity (+ or more) for at least one SSc-specific parameter (Scl70, RNA polymerase, Th/To, RP11/12, U3RNP autoantibodies) at screening or by documented medical history
4. SSC subjects: Signs for fast progression including (i) disease duration ≤ 7 years (from onset of first non-Raynaud manifestation), (ii) mRSS score 10-35 at screening, (iii) elevated acute phase reactant levels (C reactive protein [CRP] ≥ 6 mg/L, erythrocyte sedimentation rate [ESR] ≥ 28mm/h or platelet count ≥ 330 G/L), (iv) 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
5. SSC subjects: Insufficient response or intolerance/ contraindication to at least 2 of the following treatments: mycophenolate mofetil, azathioprine, cyclophosphamide, nintedanib, methotrexate, rituximab. Insufficient response is defined as having increased disease activity based on the definition explained in the previous bullet point.
6. IIM subjects: Fulfilling the 2017 ACR/EULAR classification criteria for probable or definite IIM
7. IIM subjects: Presence of active myositis in muscle biopsy or muscle MRI and/or signs of interstitial lung disease related to IIM
8. IIM: Positivity (+ or more) for at least one myositis-specific antibody (aminoacyl tRNA synthetases, Mi2, MDA5, SAE, SRP, ARS, HMGCR, MJ, TIF1gamma) at screening or by documented medical history
9. IIM subjects: In patients with active myositis: Muscle weakness as defined by MMT < 142 and 2 of the following criteria: VAS patients Global ≥ 2cm, VAS physician Global ≥ 2cm, HAQ > 0.25, at least one muscle enzyme > 1.3 times upper limit of normal, VAS global extra muscular activity ≥ 2cm
10. IIM subjects: Insufficient response or intolerance/ contraindication to glucocorticoids and to at least 2 of the following treatments: azathioprine, cyclophosphamide, mycophenolate mofetil, ciclosporin A, tacrolimus, methotrexate, rituximab, intravenous immunoglobulins. Insufficient response is defined as having increased disease activity based on the definition explained in the previous bullet point
11. Subjects must understand and voluntarily sign an informed consent form including written consent for data protection
12. Adequate renal (eGFR > 30 ml/min/m2), liver (no Child Pugh C), heart (at worst New York Heart Association [NYHA] III), ejection fraction (EF) > 30% and pulmonary (forced volume [FV] and diffusion capacity of the lungs [DLCO] ≥ 30%) function
13. 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
14. 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 index <1) starting from the time of signing the ICF and for 12 months after dosing of the IMP
15. SLE subjects: Fulfilling the 2019 ACR/EULAR classification criteria of SLE
16. SLE subjects: Positivity of anti-dsDNA (> 4 U/l), anti-histone (+ or more), anti-nucleosome (+ or more) or anti-Sm antibodies (+ or more) at screening or by documented medical history
17. SLE subjects: 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)
18. SLE subjects: Insufficient response or intolerance/ contraindication to glucocorticoids and to at least 2 of the following treatments: azathioprine, 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
19. Must be able to adhere to the study visit schedule and other protocol requirements

Exclusion criteria 17

1. Clinically suitability for a less burdensome and/or approved therapeutic approach, as judged by the investigator
2. Absolute neutrophil count (ANC) < 1.000/mm3, absolute lymphocyte count (ALC) < 500/mm3 or hemoglobin < 8g/dl
3. Uncontrolled severe concomitant disease, such as cancer (except basal or squamous cell skin cancer) and diabetes mellitus
4. Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh C), heart (NYHA IV, EF ≤ 30%) and pulmonary (FV and DLCO < 30%) function
5. 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
6. Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g., CAR T cell therapy)
7. History of bone marrow/ hematopoietic stem cell or solid organ transplantation
8. Any concomitant severe active infection, e.g. human immunodeficiency virus (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
9. Diagnosis of severe neuropsychiatric SLE, inclusion body myositis or limited SSc
10. Pregnant or lactating females
11. Females who are intending to conceive during the study
12. Known hypersensitivity to any drug components
13. Malignancy in the last 5 years before screening
14. Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis
15. 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
16. 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 (according to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG)
17. Subjects who possibly are dependent on the Sponsor, the Principal Investigator or Investigator (e.g., family members)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 21

1. • Overall Response Rate (ORR) at week 24 measured by specific disease activity composite indexes, each of them validated for the specific disease: - SLE: Fulfillment of DORIS remission criteria of SLE at week 24.
2. • Overall Response Rate (ORR) at week 24 measured by specific disease activity composite indexes, each of them validated for the specific disease: - SSc: No progression of interstitial lung disease with worsening of forced vital capacity (FVC)1 (>10%) or worsening of FVC1 (5-10%) plus increase in respiratory symptoms or worsening of FVC1 (5-10%) plus progression of high-resolution computed tomography changes after 24 weeks.
3. • Overall Response Rate (ORR) at week 24 measured by specific disease activity composite indexes, each of them validated for the specific disease: - IIM: 2016 ACR/EULAR Moderate or Major Response. 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-resolution computed tomography changes after 24 weeks.
4. • Duration of persistence of CAR T cells in the peripheral blood
5. • Duration of B cell depletion in the peripheral blood
6. • Levels of respective serum autoantibodies at week 24 including incidence of seroconversion - SLE: antinuclear antibodies (ANA), anti-double-stranded (ds)DNA, anti-nucleosomes, anti-Sm, anti-cardiolipin IgG, C3 C4
7. • Levels of respective serum autoantibodies at week 24 including incidence of seroconversion - SSc: ANA, anti-SCL70, anti-RNA polymerase III, anti-topoisomerase
8. • Levels of respective serum autoantibodies at week 24 including incidence of seroconversion - IIM: ANA, anti-Mi2, anti-Tif1, anti-MDA5, anti-Jo1, anti-NXP2
9. • Expansion of CAR T cells in the patient over time
10. • Success of the manufacturing process by Good Manufacturing Practice (GMP) certification of the product
11. • General: - Patient’s Global Assessment (PtGA) of disease activity (visual analogue scale [VAS] 0-100mm)
12. • General: - Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm)
13. • General: - Health Assessment Questionnaire – Disease Index (HAQ-DI)
14. • General: - Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT Fatigue)
15. • General: - Core Quality of Life (EORTC QLQ-C30)
16. • General: - Extension phase only: incidence and severity of Adverse Events after reduced LD
17. • SLE: - British Isles Lupus Assessment Group (BILAG) index
18. • SLE: - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)
19. • SSc: - modified Rodnan Skin Score (mRSS)
20. • IIM: - Physician’s global assessment (PhGA) of extramuscular activity
21. • IIM: - Manual Muscle Testing (MMT)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Miltenyi Biomedicine GmbH

Sponsor organisation

Miltenyi Biomedicine GmbH

Address

Friedrich-Ebert-Strasse 68, Moitzfeld Moitzfeld

City

Bergisch Gladbach

Postcode

51429

Country

Germany

Scientific contact point

Organisation

Miltenyi Biomedicine GmbH

Contact name

Clinical Trial Desk

Public contact point

Organisation

Miltenyi Biomedicine GmbH

Contact name

Clinical Trial Desk

Third parties 5

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications