A Phase 1 Study to Evaluate the Safety and Preliminary Efficacy of ATA3219, Allogeneic Anti-CD19 Chimeric Antigen Receptor T-cell (CAR T) Therapy, in Subjects With Systemic Lupus Erythematosus
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Number of Participants With treatment-emergent adverse events, including adverse events of special interest
研究概览
简要总结
The purpose of the study is to evaluate the safety and preliminary efficacy of ATA3219 (following lymphodepletion) for treatment of participants with lupus nephritis (LN).
详细描述
This is a Phase 1, multi-centered, open-labeled, dose escalation study to evaluate the safety and preliminary efficacy of ATA3219 (as monotherapy) in participants with LN. Up to 3 dose levels (DLs) will be explored in the dose escalation portion of the study and if needed a lower dose may be explored. Prior to undergoing any screening procedure, prospective participants must undergo the ATA3219 inventory check assessments to ensure availability of an appropriate partially human leukocyte antigen (HLA)-matched ATA3219 lot. Before administration of ATA3219, participants will receive conditioning chemotherapy. For all enrolled participants, hospitalization during and following ATA3219 dosing is mandatory. Participants will receive a single dose intravenous (IV) infusion of ATA3219 (monotherapy) on Day 1. Participants will remain inpatient for a minimum of 1 week post ATA3219 dosing, where they will be frequently monitored. Lupus nephritis activity will be assessed by the investigator on Day 28 (+ 5 days) following each dose of ATA3219. During dose escalation, up to 3 dose levels of ATA3219 are planned to be evaluated sequentially and a lower dose may be added. At least 3 and up to 6 dose-limiting toxicity (DLT)-evaluable participants, those who complete the 28-day DLT observation period, will be assessed at each dose level. Within each dose level, treatment will be staggered to allow appropriate safety monitoring by an independent Data Safety Monitoring Committee (DSMC).
Participants who do not receive ATA3219 for any cause may be replaced. Participants who experience an adverse event (AE) prior to completion of the 28-day DLT observation period will not be replaced. If a participant is treated with ATA3219 and discontinues for any reason other than a DLT prior to completing the 28-day DLT observation period, an additional participant may be enrolled at the dose level to ensure that the recommended phase 2 dose (RP2D) can be determined. In rare situations, retreatment of participants with inadequate renal response may be considered.
After treatment is completed or discontinued, participants will be followed for safety and renal response for up to 24 months from the last dose of ATA3219. A separate long-term follow-up study will be conducted to follow participants for up to a total of 15 years after their last dose of ATA3219.
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 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosed with SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology classification for SLE or the Systemic Lupus International Collaborating Clinics Classification criteria [Petri 2012].
- •Meets one or more of the following immunologic criteria during screening:
- •Anti double stranded DNA above laboratory reference range, except enzyme linked immunosorbent assay (2 × above laboratory reference range), OR
- •Presence of anti-Smith antibody, OR
- •Low complement as demonstrated by low complement component 3, low complement component 4, or low complement CH
- •History of International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class III or IV with or without Class V glomerulonephritis on renal biopsy either within 6 months prior to screening or as performed during screening. Biopsy should demonstrate evidence of active nephritis.
- •Proteinuria level between ≥ 1.0 to 6.0 g/day via urine protein creatinine ratio during screening.
- •Has refractory LN defined as having received 1 or more standard therapies for LN (which must have included mycophenolate mofetil, mycophenolic acid, or cyclophosphamide), and:
- •Has worsening LN (per criteria listed in [Gordon 2009]) while on treatment, OR
- •Has not achieved a complete renal response (CRR) after 2 or more lines of therapy, OR
- •Has not achieved a CRR after first-line therapy after a minimum of 12 months.
- •Is using a stable, optimized dose of a renin angiotensin system inhibitor for at least 4 weeks prior to enrollment, unless deemed inappropriate by the investigator.
- •Participants must have been previously vaccinated for pneumococcus within 5 years prior to screening (and no later than 4 weeks prior to enrollment) or be willing to receive prophylaxis against infections with encapsulated bacteria via vaccination in accordance with local standards of practice and/or guidelines.
- •Is current per national or local health authority or institutional guidelines for immunocompromised individuals on the following vaccinations, unless refused or medically contraindicated: varicella zoster (Shingrix), pneumococcal, influenza, and Corona virus disease 2019 (COVID-19).
排除标准
- •Severe kidney disease as assessed locally, defined as history of ISN/RPS Class VI or isolated Class V glomerulonephritis (without co existent/predominant Class III or IV glomerulonephritis) on renal biopsy.
- •Has a concurrent systemic autoimmune disease that may confound study assessments other than SLE, LN, or cutaneous lupus erythematosus.
- •Has any unstable or progressive manifestation of SLE that is likely to warrant an intensification of lupus-directed therapy
- •Has a history of confirmed or suspected drug-induced lupus.
- •Has a history of catastrophic antiphospholipid syndrome, or any history of prior thrombosis due to antiphospholipid syndrome resulting in hospitalization due to myocardial infarction, pulmonary embolism, or stroke.
- •Has a history of bleeding disorder requiring hospitalization or systemic therapeutic intervention within the previous 3 months, or for participants without a prior kidney biopsy meeting eligibility criterion within the past 6 months who will require a biopsy during screening, any contraindication to kidney biopsy.
- •Severe B cell immunodeficiency as evidenced by clinically significant refractory/recurrent infection.
- •Any prior cellular therapies, obinutuzumab, anti-cluster of differentiation 19 (CD19) antibody, or B-cell targeting bispecific antibody, unless B-cells have recovered to baseline as assessed by the investigator. Investigational therapies or initiation of new SLE-directed therapies within 4 weeks.
研究组 & 干预措施
Cohort LN: ATA3219 Dose Level -1
Participants will receive a single IV infusion of ATA3219 Dose Level -1 (if required) on Day 1 of a 28-day dose limiting toxicity (DLT) observation period.
干预措施: ATA3219 (Drug)
Cohort LN: ATA3219 Dose Level 1
Participants will receive a single IV infusion of ATA3219 Dose Level 1 on Day 1 of a 28-day DLT observation period.
干预措施: ATA3219 (Drug)
Cohort LN: ATA3219 Dose Level 2
Participants will receive a single IV infusion of ATA3219 Dose Level 2 on Day 1 of a 28-day DLT observation period.
干预措施: ATA3219 (Drug)
Cohort LN: ATA3219 Dose Level 3
Participants will receive a single IV infusion of ATA3219 Dose Level 3 on Day 1 of a 28-day DLT observation period.
干预措施: ATA3219 (Drug)
Cohort ERL: ATA3219 Dose Level -1
Participants will receive a single IV infusion of ATA3219 Dose Level -1 (if required) on Day 1 of a 28-day DLT observation period.
干预措施: ATA3219 (Drug)
Cohort ERL: ATA3219 Dose Level 1
Participants will receive a single IV infusion of ATA3219 Dose Level 1 on Day 1 of a 28-day DLT observation period.
干预措施: ATA3219 (Drug)
Cohort ERL: ATA3219 Dose Level 2
Participants will receive a single IV infusion of ATA3219 Dose Level 2 on Day 1 of a 28-day DLT observation period.
干预措施: ATA3219 (Drug)
Cohort ERL: ATA3219 Dose Level 3
Participants will receive a single IV infusion of ATA3219 Dose Level 3 on Day 1 of a 28-day DLT observation period.
干预措施: ATA3219 (Drug)
结局指标
主要结局
Number of Participants With treatment-emergent adverse events, including adverse events of special interest
时间窗: From administration of pretreatments (LD or methylprednisolone) through 90 days after administration of study drug
Number of Participants With Dose-limiting Toxicities
时间窗: Day 1 through Day 28 of first dose of study drug
Maximum Tolerated dose
时间窗: Day 1 through Day 28 of first dose of study drug
Recommended Phase 2 dose of ATA3219
时间窗: Day 1 through Day 28 of first dose of study drug
次要结局
- Renal Objective Response Rate(Weeks 24 and 52)
- Maximum Observed Plasma Concentration (Cmax) of ATA3219(Pre-dose on Day 1 through 24 months after the last dose on a defined schedule)
- Time to Reach Cmax (Tmax) of ATA3219(Pre-dose on Day 1 through 24 months after the last dose on a defined schedule)
- Partial Area Under the Curve (pAUC) of ATA3219(Pre-dose on Day 1 through 24 months after the last dose on a defined schedule)
- Last Observed Plasma Concentration (Clast) of ATA3219(Pre-dose on Day 1 through 24 months after the last dose on a defined schedule)
- Time of Clast of ATA3219(Pre-dose on Day 1 through 24 months after the last dose on a defined schedule)
- Partial Renal Response(Weeks 24 and 52)
- Terminal Half-life (t1/2) of ATA3219(Pre-dose on Day 1 through 24 months after the last dose on a defined schedule)
- Complete Renal Response(Weeks 24 and 52)
- Change From Baseline in Urine protein-to-Creatinine Ratio(Baseline (Day -5) through 24 months after the last dose on a defined schedule)
- Change From Baseline in Estimated Glomerular Filtration Rate(Baseline (Day -5) through 24 months after the last dose on a defined schedule)
- Duration of Urine Protein-to-Creatinine ratio ≤ 0.5(Baseline (Day -5) through 24 months after the last dose on a defined schedule)
- Change From Baseline in Lupus Low Disease Activity State (LLDAS)(Baseline (Day 28) through 24 months after the last dose on a defined schedule)
- Change From Baseline in Definition of Remission in Systemic Lupus Nephritis (DORIS)(Baseline (Day 28) through 24 months after the last dose on a defined schedule)
- Change From Baseline in the Modified Version of the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Nephritis Disease Activity (Hybrid SELENA-SLEDAI) Index(Baseline (Day 28) through 24 months after the last dose on a defined schedule)
- Change From Baseline in British Isles Lupus Assessment Group (BILAG) Index(Baseline (Day 28) through 24 months after the last dose on a defined schedule)
- Change From Baseline in SLE Responder Index (SRI)-4(Baseline (Day 28) through 24 months after the last dose on a defined schedule)
- Change From Baseline in BILAG-based Composite Lupus Assessment (BICLA) Response(Baseline (Day 28) through 24 months after the last dose on a defined schedule)
- Change From Baseline in Antibodies to Double Stranded Deoxyribonucleic Acid(Baseline (Day -5) through 24 months after the last dose on a defined schedule)
- Change From Baseline in Complement Component 3 (C3) and Complement Component 4 (C4) Levels(Baseline (Day -5) through 24 months after the last dose on a defined schedule)
- Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score(Baseline (Day 28) through 24 months after the last dose on a defined schedule)
- Number of Swollen and/or Tender Joints(Baseline (Day 28) through 24 months after the last dose on a defined schedule)