A Phase I Multicohort Trial of Zamtocabtagene Autoleucel (Zamto-Cel) in Subjects With Severe Refractory Autoimmune Diseases
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- The incidence and severity of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs)
研究概览
简要总结
AID is a phase I multi-cohort study to assess the safety and tolerability of zamtocabtagene autoleucel (zamto-cel) in patients with refractory autoimmune diseases (SLE-Non renal, SLE-LN, SSc/dcSSc) after receiving standard therapy.
详细描述
This is a Phase 1, multicohort, dose-finding study evaluating autologous T cells engineered to target dual CD19 and CD20 antigens in subjects with refractory autoimmune diseases following standard therapy. The investigational product, Zamto-cel, is a chimeric antigen receptor T-cell (CAR-T) therapy genetically engineered to enable subjects' T cells to express CARs on their surfaces.
Eligible subjects will undergo leukapheresis for the collection of cells required for manufacturing. Prior to infusion of the fresh CAR-T product, subjects will receive a lymphodepleting regimen consisting of cyclophosphamide and fludarabine. The CAR-T cell infusion will be administered intravenously at a dose of 2.5 x 10^6 or 1.0 x 10^6 CAR+ cells/kg body weight, based on the dose level assigned to the cohort.
The study will initially enroll 3 subjects per cohort in a staggered manner to evaluate safety. Upon confirmation of safety, the study will proceed to cohort-specific recommended Phase 2 dose (RP2D) and dose expansion phases. Subjects will be monitored for up to 1 year to assess safety, preliminary efficacy, and health-related quality of life (HRQoL). Additional long-term follow-up will be conducted under a separate long-term follow-up protocol.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •General Key Inclusion/
排除标准
- •Across All Cohorts
- •Inclusion Criteria:
- •Confirmed diagnosis of autoimmune disease (SLE-Non-renal, SLE-LN, SSc/ dcSSc)
- •Exclusion Criteria:
- •Prior gene therapy treatment
- •Active malignancy within past 5 years
- •Significant active fungal or bacterial infection
- •History or presence of CNS lupus or other CNS disease
- •eGFR < 45 mL/min/1.73 m^2
- •Total bilirubin outside the normal range (unless congenital hyperbilirubinemia such as Gilbert syndrome has been confirmed).
- •Systemic Lupus Erythematosus-Non-renal Key Inclusion/Exclusion Criteria
- •Inclusion Criteria:
- •Positive for at least 1 of the following autoantibodies at Screening: anti- double stranded DNA or anti-Smith
- •Systemic Lupus Erythematosus Disease Activity Index-2000 score ≥ 8 AND at least 1 British Isles Lupus Assessment Group (BILAG)-2004 Class A (severe manifestation) organ scores
- •Inadequate response to glucocorticoids and to at least 2 of the following treatments, used for at least 3 months each: cyclophosphamide, mycophenolic acid or its derivatives, belimumab, azathioprine, anifrolumab, methotrexate, rituximab, or obinutuzumab
- •Exclusion Criteria:
- •Subjects with neuropsychiatric SLE.
- •Drug-induced SLE.
- •Systemic Lupus Erythematosus - Lupus Nephritis Key Inclusion/Exclusion Criteria
- •Inclusion Criteria:
- •Positive for at least 1 of the following autoantibodies at Screening: anti- double stranded DNA or anti-Smith
- •Confirmed LN diagnosis by kidney biopsy during screening or within the previous 6 months, with severe active phase of the disease.
- •Progressing despite maintenance on maximally tolerated doses of renin- angiotensin system (RAS) blocking agents, unless allergic to or intolerant of ACE inhibitors and ARBs
- •Inadequate response to glucocorticoids and hydroxychloroquine and at least 1 of the following treatments, used for at least 3 months each: cyclophosphamide, mycophenolic acid derivatives, belimumab, azathioprine, methotrexate, rituximab, obinutuzumab, calcineurin inhibitor (cyclosporin, tacrolimus or voclosporin)
- •Exclusion Criteria:
- •Evidence of Rapidly progressive glomerulonephritis (defined as a doubling of serum creatinine within 3 months prior to enrollment) or as determined by the study investigator.
- •Systemic Sclerosis/Diffuse Cutaneous Systemic Sclerosis Cohort Key Inclusion/ Exclusion Criteria
- •Inclusion Criteria:
- •Active disease defined as:
- •Modified Rodnan skin score (mRSS) ≥ 16 units, in the prior 6 months, with 1 or more of the following:
- •Increase in mRSS by ≥ 3 units or 10%
- •Involvement of 1 new body area with increase in mRSS by ≥ 2 units
- •Involvement of 2 new body areas with increase by ≥ 1 mRSS unit OR
- •Progressive interstitial lung disease (ILD) defined as:
- •- Worsening of respiratory symptoms and an increased extent of fibrosis evaluated by high-resolution computed tomography
- •Lack of response to standard therapy (e.g., failure of ≥ 2 immunosuppressive therapies)
- •Exclusion Criteria:
- •"Active" gastric antral vascular ectasia, as evidenced by bleeding (ie, on esophagogastroduodenoscopy) in the past 6 months or as per Investigator's assessment.
- •History of SSc renal crisis within 1 year prior to Screening; presence of kidney impairment due to conditions other than SSc
研究组 & 干预措施
Dose Level 1
干预措施: zamtocabtagene autoleucel (Biological)
Dose Level 1
干预措施: Fludarabine (Drug)
Dose Level 2
干预措施: Fludarabine (Drug)
Dose Level 2
干预措施: zamtocabtagene autoleucel (Biological)
Dose Level 2
干预措施: Cyclophosphamide (Drug)
Dose Level 1
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
The incidence and severity of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs)
时间窗: From enrollment through study completion 12 months post zamto-cel infusion
The proportion of subjects with dose-limiting toxicities (DLTs) up to Day 28 and determination of recommended Phase 2 dose (RP2D)
时间窗: From enrollment through Day 28 post zamto-cel infusion
次要结局
- The incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS)(From enrollment through study completion 12 months post zamto-cel infusion)
- Clinical response at Week 4, 12, 24, and 52 evaluated by defined disease-specific activity measures in SLE-Non renal, SLE-LN, and SSc/dcSSc(From enrollment through study completion 12 months post zamto-cel infusion)
- The duration of remission or low disease activity status in respective diseases under the study(From enrollment through study completion 12 months post zamto-cel infusion)
- Persistence, maximal drug concentration (Cmax), time to reach Cmax, area under the concentration curve, and phenotype of zamto-cel(From enrollment through study completion 12 months post zamto-cel infusion)