Anti-CD 19 CAR-T cell therapy in patients with ANCA Vasculitis - the IDEAL trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Charite Universitaetsmedizin Berlin KöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Musculoskeletal Diseases [C05]

Decision date (initial)

2024-12-09

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Kyverna Therapeutics Inc.

External identifiers

EU CT number

2024-517303-36-00

ClinicalTrials.gov

NCT06590545

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

primary objective phase I: To assess the safety of anti-CD19 CAR T cell therapy in subjects with active, treatment re-fractory, ANCA-IgG-positive AAV
Co-Primary objectives phase II: To assess the safety of anti-CD19 CAR T cell therapy in subjects with active, treatment re-fractory ANCA-IgG-positive AAV 
Co-Primary objectives phase II: To assess the ANCA seroconversion rate in subjects with active, treatment refractory ANCA-IgG-positive AAV

Secondary objectives 6

1. To assess the clinical efficacy and the cellular and humoral response after anti-CD19 CAR T cell therapy
2. To analyze the changes in B cell receptor repertoire
3. To evaluate the therapy-induced changes of B cell subsets
4. Characterizing B cell and plasma cell Niches in Tissues
5. To evaluate the therapy-induced alterations of T cell compartments
6. To evaluate changes in lymphocyte numbers and composition in bone marrow biopsy, kidney biopsy, lymph node biopsy, bronchoscopic biopsy, otolaryngologic biopsy, bronchoalveolar lavage

Conditions and MedDRA coding

ANCA-IgG-positive ANCA associated vasculitis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Understand and voluntarily sign an informed consent form
2. Male or female, age ≥ 18 and ≤ 75 years at time of consent
3. Able to adhere to the study visits and protocol
4. Fulfilment of • EITHER both of the following  2022 ACR/EULAR classification criteria for granulomatosis with polyangiitis (GPA)  detectable anti-PR3 antibodies (≥ 20 AU/ml in CLIA) at screening • OR both of the following  2022 ACR/EULAR classification criteria for microscopic polyangiitis (MPA)  detectable anti-MPO antibodies (≥ 10 AU/ml in CLIA) at screening
5. Active disease, defined as Clinical activity (BVAS ≥ 3) at screening
6. Insufficient response or intolerance/contraindication to glucocorticoids and to at least one of the following treatments: rituximab, mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, avacopan. Insufficient response is defined as hav-ing disease activity based on the definition explained in the previous bullet point
7. 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
8. 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 <1) starting from the time of signing the ICF and for 12 months after dosing of the IMP
9. Updated vaccination record according to the STIKO recommendations for immuno-compromised patients
10. Additional criteria before leukapheresis: no evidence of a clinically significant active infection
11. Additional criteria before leukapheresis: negative urine pregnancy test in female patients
12. Additional criteria before leukapheresis: no clinically relevant abnormal findings on brain MRI, EEG, Echocardiogram or lung function test which would put the subject at undue risk when participating in this study
13. Additional criteria before lymphodepletion: no evidence of a clinically significant active infection
14. Additional criteria before lymphodepletion: eGFR > 30 ml/min/m2
15. Additional criteria before lymphodepletion: no acute central neurological toxicity
16. Additional criteria before lymphodepletion: negative urine pregnancy test in female patients
17. Additional criteria before lymphodepletion: notification of successful CAR T cell production by the manufacturer
18. Additional criteria before IMP administration: no evidence of a clinically significant active infection
19. Additional criteria before IMP administration: no acute central neurological toxicity

Exclusion criteria 17

1. ANC < 500/µl, ALC < 100/µl or hemoglobin < 8g/dl, absolute CD3+T cell count < 100/µl at screening
2. Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh C), or heart or pulmonary (NYHA IV, blood oxygenation < 92%) function
3. Clinically relevant rapidly progressive glomerulonephritis or pulmonary alveolar hem-orrhage
4. 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
5. Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR T cell therapy)
6. History of bone marrow/ hematopoietic stem cell or solid organ transplantation
7. 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 guide-lines must have been initiated prior to enrollment
8. Pregnant or lactating females
9. Females who are intending to conceive during the study
10. Known hypersensitivity to any drug components
11. Malignancy in the last 5 years before screening (except adequately treated basal or squamous cell skin cancer)
12. Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis,
13. Subjects who are younger than 18 years or are incapable to understand the aim, im-portance and consequences of the study and to give legal informed consent (accord-ing to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG),
14. 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 participa-tion or study agent administration, or may interfere with interpretation of results,
15. Subjects who possibly are dependent on the Sponsor, the Principal Investigator or In-vestigator (e.g. family members).
16. Subjects who are institutionalized by order of court or public authority,
17. Subjects participating in another clinical trial with an investigational medicinal product or medical device (3 months before this trial).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Safety (Phase I): Incidence and grading of severity (graded 0-4) of Cytokine Release Syndrome (CRS) and of Immune Cell Associated Neurotoxicity Syndrome (ICANS) within the first 4 weeks after anti-CD19 CAR T cell therapy.  AE and SAE due to IMP within the first 4 weeks.
2. Safety (Phase II): AE and SAE due to IMP throughout the whole study. All subjects will enter in an obligatory follow-up phase for evaluation of long-term safety lasting 15 years in total. Data will be registered in the EBMT registry after informed consent is obtained from the patients.
3. Efficacy (Phase II): Percentage of AAV subjects (GPA) with normal anti-PR3 antibodies (< 20 AU/ml) and AAV subjects (MPA) with normal anti-MPO antibodies (< 10 AU/ml) at week 24.

Secondary endpoints 27

1. Survival time without immunosuppression from week 9 to week 52
2. Time to relapse/flare from week 9 to week 52
3. Percentage of patients who reach EULAR response criteria (≥ 50% reduction of Birmingham Vasculitis Activity Score (BVAS) at week 12, 24 and 52) compared to baseline
4. Percentage of patients who reach EULAR sustained remission criteria (Absence of typical signs, symptoms, or other features of active AAV) through week 52
5. Change of Vasculitis Damage Index (VDI) at week 12, 24 and 52 compared to baseline
6. Change in Birmingham Vasculitis Activity Score (BVAS) at week 12, 24 and 52 compared to baseline
7. Number of flares through week 12, 24 and 52 weeks
8. Percentage of subjects with normal anti-PR3 antibodies (< 20 U/ml) at week 12 and 52 (GPA).
9. Percentage of subjects with normal anti-MPO antibodies (< 10 U/ml) at week 12 and 52 (MPA).
10. Duration of persistence of CAR T cells in the peripheral blood
11. Duration of B cell depletion in the peripheral blood
12. Expansion of CAR T cells in the patient over time
13. Change in anti-PR3 antibodies over time (GPA)
14. Change in anti-MPO antibodies over time (MPA)
15. Change in total IgG, IgG subclasses and IgA, IgM immunoglobulins over time
16. Change in MPO (MPA) or PR3 (GPA) specific plasmablasts and B-cells
17. Change in the number of plasmablasts, B cell and T cell numbers over time
18. Patient’s Global Assessment (PtGA) of disease activity (VAS 0-100mm)
19. Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm)
20. European Quality of Life 5 Dimensions (EQ-5D)
21. Short Form 36 (SF-36, quality of life questionnaire)
22. ANCA-associated vasculitis patient reported outcome (AAV-PRO)
23. To analyze the changes in B cell receptor repertoire
24. To evaluate the therapy-induced changes of B cell subsets
25. Characterizing B Cell and Plasma Cell Niches in Tissues
26. To evaluate the therapy-induced alterations of T cell compartments
27. To evaluate changes in kidney biopsy from baseline to week 52 (optional)

Investigational products

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

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Charite Universitaetsmedizin Berlin KöR

Sponsor organisation

Charite Universitaetsmedizin Berlin KöR

Address

Chariteplatz 1, Mitte Mitte

City

Berlin

Postcode

10117

Country

Germany

Scientific contact point

Organisation

Charite Universitaetsmedizin Berlin KöR

Contact name

Dr. David Simon

Public contact point

Organisation

Charite Universitaetsmedizin Berlin KöR

Contact name

Dr. David Simon

Third parties 4

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

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

Documents 5 files

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

Application history

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