NCT04796688Unknown1 期
Safety and Efficacy of Universal Chimeric Antigen Receptor-modified AT19 Cells in Patients With CD19+ Relapsed/Refractory Hematological Malignancies: a Single-center, Open-label, Single-arm Clinical Study
Wuhan Union Hospital, China1 个研究点 分布在 1 个国家目标入组 27 人开始时间: 2021年3月10日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Incidence of Treatment-related Adverse Events
研究概览
简要总结
This is a single-center, open-label, single-arm study to evaluate the primary safety and efficacy of universal chimeric antigen receptor-modified AT19 cells in patients with relapsed or refractory hematological malignancies.
详细描述
- Adoptive transfer of autologous anti-CD19 CAR-T cells can induce durable remissions in patients with relapsed/refractory hematologic malignancies, including CD19+ B-cell acute lymphoblastic leukemia(B-ALL), B-cell chronic lymphoblastic leukemia(B-CLL), and B-cell lymphoma.
- However, multiple challenges exist for manufacturing CAR-T cells from patients with advanced disease including inability to manufacture a product, disease progression or death while waiting for the CAR-T product to be available, and heterogeneity among autologous CAR-T products that contributes to unpredictable and variable clinical activity.
- Healthy donor T cells can provide a source for production of universal CAR-T cells when combined with gene editing to prevent expression of endogenous TCRs and avoid generation of GvHD in HLA mismatched recipients.
- Cord blood derived T cells from healthy donor are the source for production of universal anti-CD19 CAR-modified AT19 cells. CRISPR/cas9 gene-editing technology has been used to knockout TCRs and HLA-I to avoid GvHD and transplant rejection.
- AT19 cells have exhibited potent cytotoxicity in CD19+ tumor cells and can effectively eradicate CD19+ tumor cells in xenograft mice models, without showing GvHD.
- This study aims to evaluate prelimary safety and efficacy of the universal AT19 cells in patients with relapsed/refractory B-ALL, B-CLL, and B-cell lymphoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 78 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 14-78 years old (including 14 and 78 years old).
- •Clinical diagnosis of CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and lymphoma.
- •Refractory/Relapsed B-cell malignancies:
- •A. Refractory/relapsed B-cell lymphoblastic leukemia, meeting one of the following criteria:
- •i. Recurrence within 6 months after first remission. ii. Primary refractory disease which cannot achieve complete remission (CR) after 2 cycles of standardized chemotherapy regimen.
- •iii. Failure to achieve CR or relapse after one line or multiple lines of salvage chemotherapy.
- •iv. Not suitable for hematopoietic stem cell transplantation (HSCT), or abandon HSCT due to various restrictions, or relapse after HSCT.
- •B. Refractory/relapsed B-cell lymphoma, meeting 1 of the first 4 items plus item 5: i. Tumor shrinkage less than 50% or disease progression after 4 cycles of standard chemotherapy.
- •ii. Achieved CR after standard chemotherapy, but relapsed within 6 months. iii. 2 or more relapses after CR. iv. Not suitable for HSCT, or abandon HSCT due to various restrictions, or relapse after HSCT.
- •v. Subjects must have received adequate treatment in the past, including anti-CD20 monoclonal antibody and combination chemotherapy with anthracyclines.
- •Having a measurable or evaluable lesion:
- •A. Patients with lymphoma require a single lesion≥15mm or 2 or more lesions≥10mm.
- •B. Patients with leukemia require persistent positive or positive relapse of bone marrow MRD.
- •The toxicity related to previous treatments had returned to < 1 level at enrollment (except for low grade toxicity such as alopecia).
- •Patients have good main organs functions:
- •A. Liver function: ALT/AST < 2.5 times the upper limit of normal (ULN) and total bilirubin≤ 1.5 times ULN; B. Renal function: Creatinine clearance rate ≥ 60ml/min. C. Pulmonary function: Indoor oxygen saturation ≥ 95%. D. Cardiac Function: Left ventricular ejection fraction (LVEF) ≥50%, no clinically-significant ECG findings.
- •Estimated survival time≥3 months.
- •Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.
排除标准
- •Central nervous system is involved in leukemia and lymphoma.
- •Known HIV positive patients.
- •CNS diseases, such as epilepsy, cerebral ischemia / hemorrhage, dementia, cerebellar diseases or any CNS related autoimmune diseases.
- •NYHA class III or higher cardiac failure, or with malignant arrhythmia.
- •Myocardial infarction, angioplasty or stent placement, unstable angina or other clinically significant heart history within 12 months before enrollment.
- •Patients who need immediate treatment to control tumor progression or relieve tumor burden.
- •Active autoimmune diseases requiring systemic immunosuppressive therapy.
- •History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months before enrollment.
- •Severe immediate hypersensitivity to any drug to be used in this study.
- •Women who are pregnant or breastfeeding.
- •Other unsuitable conditions in the researchers' opinion.
研究组 & 干预措施
Fludarabine + Cyclophosphamide + AT19 cells
Experimental
Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (300 mg/kg) on days -5, -4, and -3, followed by the infusions of AT19 cells on day 0-2. The study will be divided into three groups: B-ALL, B-CLL, and B-cell lymphoma. Doses of 0.5×10^7, 1.0×10^7, and 2.0×10^7 CAR+ T cells (with an allowance of ±20%) will be tested in each group in the 3+3 dose-escalation study. Each dose group has 3 patients. If no DLT emerges in the group, then the next group uses the subsequent higher dose. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level.The maximum dose could be extended.
干预措施: Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells (Drug)
结局指标
主要结局
Incidence of Treatment-related Adverse Events
时间窗: within 2 years after infusion
Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).
次要结局
- Complete response rate(CRR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(within 2 years after infusion)
- Progress-free survival(PFS) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(2 years after infusion)
- Duration of Response(DOR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(2 years after infusion)
- Overall survival(OS) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(2 years after infusion)
- Overall response rate(ORR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(within 2 years after infusion)
研究者
MEI HENG
Proferssor, Cheif Doctor
Wuhan Union Hospital, China
研究点 (1)
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