Anti-CD 19 CAR-T cell therapy in patients with ANCA Vasculitis: A two-stage interventional, prospective, open-label, phase I/II trial in patients with active, treatment refractory, ANCA-IgG-positive vasculitis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- 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.
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
结局指标
主要结局
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.
次要结局
- Survival time without immunosuppression 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 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 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
- 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).
- Duration of persistence of CAR T cells in the peripheral blood
- Duration of B cell depletion in the peripheral blood
- Expansion of CAR T cells in the patient over time
- Change in anti-PR3 antibodies over time (GPA)
- Change in anti-MPO antibodies over time (MPA)
- 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 the number of plasmablasts, B cell and T cell numbers over time
- Patient’s Global Assessment (PtGA) 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)
- Short Form 36 (SF-36, quality of life questionnaire)
- ANCA-associated vasculitis patient reported outcome (AAV-PRO)
- To analyze the changes in B cell receptor repertoire
- To evaluate the therapy-induced changes of B cell subsets
- Characterizing B Cell and Plasma Cell Niches in Tissues
- To evaluate the therapy-induced alterations of T cell compartments
- To evaluate changes in kidney biopsy from baseline to week 52 (optional)
研究者
Dr. David Simon
Scientific
Charite Universitaetsmedizin Berlin KöR