CARTIMMUNE: A Single-Center Study of Patients With Autoimmune Diseases Receiving an Autologous Fully-Human Anti-CD19 Chimeric Antigen Receptor T-Cell (KYV 101)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Incidence and severity of AEs in IIM.
研究概览
简要总结
The purpose of this study is to assess the safety, tolerability, and clinical activity of KYV 101 (a fully-human anti-CD19 CAR T-cell therapy) in adult subjects with B cell-driven autoimmune diseases. The trial anticipates enrolling participants to reach a maximum of 24 participants who will receive 1 dose of KYV-101 and will be followed for 2 years.
详细描述
The purpose of this study is to assess the safety, tolerability, and clinical activity of KYV 101 (a fully-human anti-CD19 CAR T-cell therapy) in 24 adult subjects with B cell-driven autoimmune diseases. The diseases under study include: idiopathic necrotizing myopathy (INM) consisting of dermatomyositis (DM), necrotizing myopathy, anti-HMGCoA-associated myopathy, and polymyositis (PM), diffuse cutaneous systemic sclerosis (dcSSc), systemic lupus erythematosus (SLE) with nephritis, and ANCA-associated vasculitis (AAV).
Six participants in each autoimmune disease group for a total of 24 participants will receive a single dose of 1.0×10[8] CAR+ T cells. Participants will be followed under this protocol for 2 years.
Lymphodepleting chemotherapy of cyclophosphamide (CYC) 300 mg/m2 and fludarabine (FLU) 30 mg/m2 intravenously (IV) daily for 3 days will be administered 5 to 7 days prior to administration of KYV-101.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Idiopathic inflammatory myopathy (including dermatomyositis, antisynthetase syndrome, immune mediated necrotizing myopathy, and polymyositis):
- •Diagnosis of probable or definite (>55%) idiopathic inflammatory myopathy, including dermatomyositis, anti-synthetase myopathy, immune-mediated necrotizing myopathy (including anti-HMGCoR-myopathy, anti-SRP myopathy), polymyositis, according to the 2017 ACR/EULAR Classification Criteria for idiopathic inflammatory myopathies (Lundberg, Tjarnlund et al. 2017).
- •Disease severity and minimal core set measure criteria: MMT-8 score <136/150, with at least 2 other abnormal core set measures (CSMs) from the following:
- •Patient global VAS≥3 on a 1-10 scale (Appendix 3).
- •Physician's global VAS ≥3 on a 1-10 scale (Appendix 4).
- •Global extramuscular activity score ≥2 cm (Appendix 5).
- •Elevation of at least one of the muscle enzymes (CK, AST, ALT, aldolase, LDH) >1.5 times upper limit of normal (Appendix 6).
- •HAQ-DI ≥0.25 (Appendix 7).
- •Active disease as per one of the following:
- •Creatine kinase ≥4×ULN.
- •Active rashes of dermatomyositis such that CDASI-activity ≥6 (Appendix 8).
- •Evidence on MRI of active myositis within last 6 months.
- •Evidence on EMG of active myositis within last 6 months.
- •Muscle biopsy evidence of active myositis within last 6 months
- •Positive, at screening or by documented medical history, for one myositis-specific per pre specified list (Table 3), except for patients with DM who need not have a positive test for a myositis-specific antibody.
- •Pre specified List of Autoantibodies
- •Myositis-specific: Target Antigen
- •Anti-Jo-1: Histidyl-tRNA synthetase
- •Anti-EJ: Glycyl-tRNA synthetase
- •Anti-PL-7: Threonyl-tRNA synthetase
- •Anti-OJ: Isoleucyl-tRNA synthetase
- •Anti-PL-12: Alanyl-tRNA synthetase
- •Anti-Mi-2: Nucleosome remodeling deacetylase complex
- •Anti-TIF1 gamma; Transcription intermediary factor 1
- •Anti-MDA5: Melanoma differentiation associated protein 5
- •Anti-SAE: Small ubiquitin-like modifier activating enzyme
- •Anti-NXP2: Nuclear matrix protein 2
- •Anti-SRP: Signal recognition particle
- •Anti-HMGCR: 3hydroxy-3methylglutaryl CoA reductase
- •Refractory disease: subject with previous failure (or intolerance) to glucocorticoids and at least two non-glucocorticoids immunosuppressive therapies. An adequate trial of medication defined as at least 12 weeks of therapy or intolerance/adverse reaction necessitating discontinuation.
- •Diffuse cutaneous systemic sclerosis:
- •Classified as systemic sclerosis according to the 2013 ACR/EULAR classification criteria, with a total score of ≥
- •Clinical disease as follows:
- •Classified as diffuse cutaneous SSc.
- •6 years or less since first non-Raynaud's sign or symptom.
- •Active disease defined as:
- •MRSS ≥16 with, in the prior 6 months, one or more of the following:
- •An increase in MRSS of ≥3 units
- •Involvement of 1 new body area with ≥2 MRSS units
- •2 new body areas with ≥1 MRSS unit. OR
- •Progressive ILD meeting all of the following criteria
- •Inadequate response or intolerance to at least one treatment, including cyclophosphamide, methotrextate, MMF/mycophenolic acid, nintedanib, rituximab, or tocilizumab.
- •AND one of the following:
- •Evidence of progression on HRCT
- •FVC <80%
- •DLCO <80%
- •evidence of FVC decline of 10% (absolute decline)
- •FVC decline of 5% to 9% and DLCO 15%.
- •SLE-related nephritis:
- •Clinical diagnosis of SLE consistent with the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria.
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排除标准
- •Autoimmune Disease-Related Exclusion Criteria
- •Idiopathic inflammatory myopathy:
- •1a. Evidence of any of the following:
- •Severe muscle damage as per one of the following criteria:
- •Myositis Global Damage Index (MDI) ≥
- •Severe proximal muscle atrophy of upper or lower extremity on MRI.
- •Severe proximal muscle atrophy of upper or lower extremity on clinical examination.
- •Wheelchair-bound at home.
- •MMT-8 of ≤
- •MDA5-positive rapidly progressing disease (subjects with stable ILD not requiring supplemental oxygen are eligible).
- •Findings of muscular inflammation or myopathy other than the indication, such as inclusion body myositis (IBM), cancer-associated myositis (myositis diagnosed within 2 years of cancer), drug-induced myopathy, amyloid myopathy, muscular dystrophy, metabolic myopathies, or myositis in the context of significant overlap with another systemic autoimmune rheumatologic disease (overlap myositis), except with Sjögren's syndrome.
- •Patients with ILD requiring O2 therapy and/or FVC ≤45% of predicted.
- •Generalized, severe musculoskeletal or neuro-muscular conditions other than IIM that prevent a sufficient assessment of the patient by the physician.
- •Diffuse cutaneous systemic sclerosis:
- •1.b. Subject with any of the following:
- •Patients with ILD with any of the following
- •Requiring O2 therapy and/or FVC ≤45% of predicted or DLCO ≤40% of predicted at screening
- •Evidence of PAH as defined as estimated RVSP or ≥45 mmHg or right atrial or ventricular enlargement or dilatation, unless subsequent RHC shows no PAH.
- •PAH on right heart catheterization requiring PAH specific treatment.
- •Active bleeding related to gastric antral vascular ectasia (GAVE) in past 6 months.
- •Gastrointestinal dysmotility requiring total parenteral nutrition (TPN).
- •Renal crisis within 1 year prior to enrollment.
- •Pericardial tamponade within 6 months prior to enrollment.
- •Active infection of a digital ulcer within 3 months prior to enrollment.
- •Current gangrene of a digit
- •SLE-related nephritis:
- •1.c. Subject with any of the following:
- •Evidence of rapidly progressive glomerulonephritis (defined as a doubling of serum creatinine within 3 months prior to enrollment).
- •History of or currently active severe CNS lupus, including cerebritis, cerebrovascular accident (CVA), and seizures. Presence of active neuropsychiatric lupus as assessed by a neurologist and a rheumatologist (at time of screening or during screening period).
- •Patients with volume overload inadequately controlled by a stable dose of diuretics
- •ANCA-associated vasculitis:
- •d. Subject with any of the following acute manifestations of ANCA-associated vasculitis:
- •Alveolar hemorrhage requiring pulmonary ventilation support.
- •Respiratory failure
- •Spinal cord lesion
- •Stroke Abbreviations: CNS=central nervous system; CVA=cerebral vascular accident; DLCO=diffusing capacity of lung for carbon monoxide; FVC=forced vital capacity; ILD=interstitial lung disease; MDI=Myositis Damage Index; MRI=magnetic resonance imaging; PAH=pulmonary arterial hypertension; RHC=right heart catheterization; RSVP=right ventricular systolic pressure
- •Other Exclusion Criteria
- •Prior treatment with cellular immunotherapy (eg, CAR T) or gene therapy product directed at any target.
- •Positive hepatitis B surface antigen (HBsAg) and hepatitis C serology confirmed by polymerase chain reaction (PCR) (except hepatitis C cured with pharmacotherapy); subjects who are HBsAg negative and hepatitis B core antibody (HBc) positive with no detectable DNA will be allowed into the study but will require regular monitoring of hepatitis B virus (HBV) DNA.
- •Positive serology for human immunodeficiency virus (HIV).
- •Primary immunodeficiency.
- •History of other autoimmune disorders other than the target disease requiring immunosuppressve therapies.
- •History of stroke, seizure, dementia, Parkinson's disease, coordination movement disorder, cerebellar diseases, psychosis, paresis, aphasia, and any other neurologic disorder investigator considers would increase the risk for the subject.
- •Subjects who have central nervous system manifestations of the target disease condition i.e., Idiopathic inflammatory myopathy, Diffuse cutaneous systemic sclerosis, SLE, ANCA-associated vasculitis.
- •Impaired cardiac function or clinically-significant cardiac disease including:
- •a. Unstable angina or myocardial infarction or coronary artery bypass graft (CABG) within 6 months prior to leukapheresis.
- •b. New York Heart Association (NYHA) stage III or IV congestive heart failure. c. History of clinically significant cardiac arrhythmia (eg, ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block.
- •d. History of severe ischemic or nonischemic cardiomyopathy. e. Left ventricular ejection fraction (LVEF) <40% as assessed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan (performed ≤8 weeks of leukapheresis).
- •Previous or concurrent malignancy with the following exceptions:
- •Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to screening).
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研究组 & 干预措施
IIM
Participants with idiopathic inflammatory myopathy will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: KYV-101 (Drug)
IIM
Participants with idiopathic inflammatory myopathy will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: Cyclophosphamide (Drug)
IIM
Participants with idiopathic inflammatory myopathy will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: Fludarabine (Drug)
DCSS
Participants with diffuse cutaneous systemic sclerosis will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: KYV-101 (Drug)
DCSS
Participants with diffuse cutaneous systemic sclerosis will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: Cyclophosphamide (Drug)
DCSS
Participants with diffuse cutaneous systemic sclerosis will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: Fludarabine (Drug)
SLE
Participants with SLE-related nephritis will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: KYV-101 (Drug)
SLE
Participants with SLE-related nephritis will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: Cyclophosphamide (Drug)
SLE
Participants with SLE-related nephritis will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: Fludarabine (Drug)
AAV
Participants with ANCA-associated vasculitis will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: KYV-101 (Drug)
AAV
Participants with ANCA-associated vasculitis will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: Cyclophosphamide (Drug)
AAV
Participants with ANCA-associated vasculitis will receive will receive lymphodepleting chemotherapy of cyclophosphamide and fludarabine prior to administration of KYV-101.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Incidence and severity of AEs in IIM.
时间窗: 24 months after CAR infusion.
Incidence and severity of AEs in Idiopathic inflammatory myopathies.
Incidence and severity of AEs in DCSS
时间窗: 24 months after CAR infusion.
Incidence and severity of AEs in diffuse cutaneous systemic sclerosis
Incidence and severity of AEs in AAV
时间窗: 24 months after CAR infusion.
Incidence and severity of AEs in ANCA-Associated vasculitis
Incidence and severity of AEs in SLE Nephritis
时间窗: 24 months after CAR infusion.
Incidence and severity of AEs in systemic lupus erythematosus nephritis.
Incidence and severity of AEs in DCSS
时间窗: 12 months after CAR infusion.
Incidence and severity of AEs in diffuse cutaneous systemic sclerosis
Incidence and severity of AEs in SLE Nephritis
时间窗: 3 months after CAR infusion.
Incidence and severity of AEs in systemic lupus erythematosus nephritis.
Incidence and severity of AEs in SLE Nephritis
时间窗: 6 months after CAR infusion.
Incidence and severity of AEs in systemic lupus erythematosus nephritis.
Incidence and severity of AEs in SLE Nephritis
时间窗: 12 months after CAR infusion.
Incidence and severity of AEs in systemic lupus erythematosus nephritis.
Incidence and severity of AEs in AAV
时间窗: 3 months after CAR infusion.
Incidence and severity of AEs in ANCA-Associated vasculitis
Incidence and severity of AEs in AAV
时间窗: 6 months after CAR infusion.
Incidence and severity of AEs in ANCA-Associated vasculitis
Incidence and severity of AEs in AAV
时间窗: 12 months after CAR infusion.
Incidence and severity of AEs in ANCA-Associated vasculitis
Incidence and severity of AEs in IIM.
时间窗: 3 months after CAR infusion.
Incidence and severity of AEs in Idiopathic inflammatory myopathies
Incidence and severity of AEs in IIM.
时间窗: 6 months after CAR infusion.
Incidence and severity of AEs in Idiopathic inflammatory myopathies.
Incidence and severity of AEs in IIM.
时间窗: 12 months after CAR infusion.
Incidence and severity of AEs in Idiopathic inflammatory myopathies.
Incidence and severity of AEs in DCSS
时间窗: 3 months after CAR infusion.
Incidence and severity of AEs in diffuse cutaneous systemic sclerosis
Incidence and severity of AEs in DCSS
时间窗: 6 months after CAR infusion.
Incidence and severity of AEs in diffuse cutaneous systemic sclerosis
次要结局
未报告次要终点
研究者
David Porter
Director, Cell Therapy and Transplant, University of Pennsylvania
University of Pennsylvania