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

Phase 1/2

Not yet recruiting

• Conditions: ANCA-IgG-positive ANCA associated vasculitis

• Registration Number: 2024-517303-36-00
• Lead Sponsor: Charite Universitaetsmedizin Berlin KöR

Brief Summary

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

Detailed Description

This study aims to investigate the use of KYV101 (a fully human anti-CD19 CAR T cell therapy) in ANCA-IgG-positive AAV patients who are refractory to previous treatments. This study is designed to determine (i) the safety of this B-cell targeted therapy, (ii) the clinical efficacy, (iii) the impact on the immunological status of the patient and in particular on ANCA positivity, and (iv) the ability to induce long-term (deep) clinical and molecular remission and drug-free survival.

The investigational product (IMP), KYV-101, is an autologous fully-human anti-CD19 CAR T-cell immunotherapy. Before IMP infusion, patients will receive a premedication of 4 mg Dimetindenmaleat iv or equivalent antihistamine and 1000 mg oral acetaminophene. Prophylactic doses of acyclovir of 400mg 2x daily as well as cotrimoxazole 960mg 3x weekly will be administered orally following CAR T cell infusion until week 24. Tocilizumab 8mg/kg will be administered intravenously when required for treatment of IMP-related cytokine release syndrome. Dexamethasone as needed will be administered intravenously when required for treatment of neurological adverse event (ICANS).

Follow-up time is 52 weeks with regular visits at the site.

Study Timeline

• Study First Posted: 2024-12-09
• Last Update Posted: 2024-12-09

Recruitment & Eligibility

• Status: Authorised, recruitment pending
• Sex: Not specified
• Target Recruitment: 8

Inclusion Criteria

Understand and voluntarily sign an informed consent form

Additional criteria before leukapheresis: no evidence of a clinically significant active infection

Additional criteria before leukapheresis: negative urine pregnancy test in female patients

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

Additional criteria before lymphodepletion: no evidence of a clinically significant active infection

Additional criteria before lymphodepletion: eGFR > 30 ml/min/m2

Additional criteria before lymphodepletion: no acute central neurological toxicity

Additional criteria before lymphodepletion: negative urine pregnancy test in female patients

Additional criteria before lymphodepletion: notification of successful CAR T cell production by the manufacturer

Additional criteria before IMP administration: no evidence of a clinically significant active infection

Additional criteria before IMP administration: no acute central neurological toxicity

Male or female, age ≥ 18 and ≤ 75 years at time of consent

Able to adhere to the study visits and protocol

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

Active disease, defined as Clinical activity (BVAS ≥ 3) at screening

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

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 <1) starting from the time of signing the ICF and for 12 months after dosing of the IMP

Updated vaccination record according to the STIKO recommendations for immuno-compromised patients

Exclusion Criteria

ANC < 500/µl, ALC < 100/µl or hemoglobin < 8g/dl, absolute CD3+T cell count < 100/µl at screening

Known hypersensitivity to any drug components

Malignancy in the last 5 years before screening (except adequately treated basal or squamous cell skin cancer)

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, 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),

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,

Subjects who possibly are dependent on the Sponsor, the Principal Investigator or In-vestigator (e.g. family members).

Subjects who are institutionalized by order of court or public authority,

Subjects participating in another clinical trial with an investigational medicinal product or medical device (3 months before this trial).

Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh C), or heart or pulmonary (NYHA IV, blood oxygenation < 92%) function

Clinically relevant rapidly progressive glomerulonephritis or pulmonary alveolar hem-orrhage

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 guide-lines must have been initiated prior to enrollment

Pregnant or lactating females

Females who are intending to conceive during the study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Primary Outcome Measures

Name	Time	Method
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.		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.
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.		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.
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.		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 Outcome Measures

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

Trial Locations

Locations (1)

Charite Universitaetsmedizin Berlin KöR; 🇩🇪 Berlin, Germany

Charite Universitaetsmedizin Berlin KöR

🇩🇪Berlin, Germany

David Simon

Site contact

+4930450513025

david.simon@charite.de