Anti-CD 19 CAR-T Cell Therapy in Patients with ANCA Vasculitis
- Conditions
- ANCA-IgG-positive ANCA Associated Vasculitis
- Interventions
- Drug: KYV-101, an autologous fully-human anti-CD19 CAR T-cell immunotherapy
- Registration Number
- NCT06590545
- Lead Sponsor
- David Simon
- Brief Summary
The goal of this phase I/II clinical trial is to investigate anti-CD 19 chimeric antigen receptor T cell (CAR-T cell) therapy in patients with antineutrophil cytoplasmic antibodies (ANCA) immunoglobulin (IgG) positive ANCA associated vasculitis (AAV).
The main questions it aims to answer are:
* To assess the safety of anti-CD19 CAR-T cell therapy in subjects with active, treatment refractory, ANCA-IgG-positive AAV
* To assess the clinical efficacy of anti-CD19 CAR-T cell therapy in subjects with active, treatment refractory ANCA-IgG-positive AAV
* To assess the ANCA seroconversion rate in subjects with active, treatment refractory ANCA-IgG-positive AAV
Participants will receive a single dose of KYV-101 i.v., an autologous fully-human anti-CD19 CAR-T cell immunotherapy. Follow-up time is 52 weeks with regular visits at the site.
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 8
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Understand and voluntarily sign an informed consent form
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Male or female, age ≥ 18 and ≤ 75 years at ti me of consent
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Able to adhere to the study visits and protocol
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Fulfilment of
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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
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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
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Active disease, defined as Clinical activity (BVAS ≥ 3) at screening
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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 having disease activity based on the definition explained in the previous bullet point
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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
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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 less than 1) starting from the time of signing the ICF and for 12 months after dosing of the IMP
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Updated vaccination record according to the STIKO recommendations for immuno-compromised patients
- ANC less than 500/µl, ALC less than 100/µl or hemoglobin less than 8g/dl, absolute CD3+T cell count less than 100/µl at screening
- Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh C), or heart or pulmonary (NYHA IV, blood oxygenation less than 92%) function
- Clinically relevant rapidly progressive glomerulonephritis or pulmonary alveolar hemorrhage
- 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
- 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, importance 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 Investigator (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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description KYV-101, anti-CD19 CAR T-cell immunotherapy. KYV-101, an autologous fully-human anti-CD19 CAR T-cell immunotherapy A dosage of 1x10\^8 KYV-101 CAR+ T cells will be administered intravenously as a single infusion.
- Primary Outcome Measures
Name Time Method number of subjects experiencing a cytokine release syndrome Screening up to week 4 The primary safety outcome in Phase I variable will be measured as the number of subjects experiencing a cytokine release syndrome (CRS) or an immune cell-associated neurotoxicity syndrome (ICANS) as well as adverse events (AE) and serious adverse events (SAE) due to investigational medical product (IMP) within the first 4 weeks.
antineutrophil cytoplasmic antibodies (ANCA) seroconversion rate week 24 The primary efficacy outcome variable of Phase II will be the antineutrophil cytoplasmic antibodies (ANCA) seroconversion rate in subjects with active, treatment refractory ANCA-IgG-positive AAV at week 24.
adverse events and serious adverse events due to investigational medical product up to 52 weeks The primary safety outcome variable of Phase II will be measured as adverse events (AE) and serious adverse events (SAE) due to investigational medical product (IMP) throughout the whole study.
- Secondary Outcome Measures
Name Time Method immunoglobulin IgG up to week 52 Change in total IgG immunoglobulins over time
immunoglobulin IgG subclasses up to week 52 Change in total IgG subclasses mmunoglobulins over time
immunoglobulin IgA up to week 52 Change in total IgA immunoglobulins over time
immunoglobulin IgM up to week 52 Change in total IgM immunoglobulins over time
Change in PR3 up to week 52 Change in PR3 specific plasmablasts and B-cells
Change in MPO up to week 52 Change in MPO specific plasmablasts and B-cells
number of plasmablasts up to week 52 Change in the number of plasmablasts cell over time
number of B cells up to week 52 Change in the number of pB cells numbers over time
number of T cells up to week 52 Change in the number T cells numbers over time
relapse/flare up to 52 weeks Time to relapse/flare
time without immunosuppression up to 52 weeks Survival time without immunosuppression
Vasculitis Damage Index up to 52 weeks Change of Vasculitis Damage Index (VDI) compared to baseline
Flares up to 52 weeks Number of flares
Birmingham Vasculitis Activity Score up to 52 weeks Change in Birmingham Vasculitis Activity Score (BVAS) compared to baseline
B cell depletion up to 52 weeks Duration of B cell depletion in the peripheral blood
persistence of CAR T cells up to 52 weeks Duration of persistence of CAR T cells in the peripheral blood
Change in anti-PR3 antibodies up to 52 weeks Change in anti-PR3 antibodies over time (GPA)
anti-MPO antibodies up to week 52 Percentage of subjects with normal anti-MPO antibodies (less than 10 AU/ml)
normal anti-PR3 antibodies up to 52 weeks Percentage of subjects with normal anti-PR3 antibodies (less than 20 AU/ml in CLIA)
EULAR sustained remission criteria up to week 52 Percentage of patients who reach European Alliance of Associations for Rheumatology (EULAR) sustained remission criteria (absence of typical signs, symptoms, or other features of active ANCA associated vasculitis)
reach EULAR response criteria up to 52 weeks Percentage of patients who reach European Alliance of Associations for Rheumatology (EULAR) response criteria (≥ 50% reduction of Birmingham Vasculitis Activity Score (BVAS) compared to baseline
number of CAR-T cells up to 52 weeks number of CAR-T cells in the patient over time