Safety and Efficacy of Cord Blood Derived Anti-CD19 CAR-Engineered NK Cells for Relapsed/Refractory B Lymphoid Malignancies: a Single-center, Open-label, Single-arm Clinical Study
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 anti-CD19 chimeric antigen receptor(CAR)-modified NK cells(CAR-NK-CD19) in patients with relapsed or refractory hematological malignancies.
详细描述
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
Cord blood(CB) derived NK cells from healthy donor are the source for production of CAR-NK-CD19 cells. CB derived NK cells are purified and transduced with a retroviral vector encoding the anti-CD19 CAR and interleukin-15.
This is an investigational study. The objectives are to evaluate the safety and efficacy of CAR-NK-CD19 cells in patients with CD19+ B-cell malignancies.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged ≥ 18 years;
- •Eastern Cooperative Oncology Group score≤ 3;
- •Diagnosed as CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and Non Hodgkin's lymphoma.
- •Patients must relapse or be refractory after at least two lines of therapy.
- •Patient's main organs functioning well:
- •A. Liver function: alanine aminotransferase/aspartate aminotransferase < 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.
- •Negativity of blood pregnancy test for woman, and participants use effective methods of contraception until last follow-up.
- •Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.
排除标准
- •Investigators judge the patients with gastrointestinal lymph node and/or central nervous system involvement who may be at high-risk of receiving CAR-NK-CD19 cell treatment.
- •Patients with graft-versus-host reaction and need immunosuppressive agents, or patients with autoimmune diseases.
- •Systemic steroids are used within 5 days before apheresis.
- •Drugs to stimulate the production of bone marrow hematopoietic cells are used within 5 days before apheresis.
- •Patients receive cytotoxic chemotherapy or radiotherapy within 21 days before enrollment(Tyrosine kinase inhibitors or other targeted therapies can be used two weeks before lymphodepleting chemotherapy).
- •History of epilepsy or other central nervous system diseases.
- •Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within five years.
- •Known HIV positive patients.
- •Patients with active infections, including active replication of hepatitis B or active hepatitis C.
- •Patients receive any antitumor treatments within 4 weeks before enrollment, and the toxicity related to previous treatments don't return to < 1 level at enrollment (except for low grade toxicity such as alopecia).
- •Major surgery in the past 4 weeks.
- •Non-compliant patients.
- •Anticoagulants are being used.
研究组 & 干预措施
Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells
Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (300 mg/kg) on day -5, -4, and -3, followed by one infusion of CAR-NK-CD19 cells on day 0. The study will be divided into three groups: Acute Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, and Non Hodgkin's Lymphoma. Doses of 0.01×10^7, 0.1×10^7, 1.0×10^7 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 dose-limited toxicity (DLT) emerges in the group, then the subsequent higher dose will be used in the next group. 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
- Progress-free survival(PFS) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(within 2 years after infusion)
- Overall response rate(ORR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(within 2 years after infusion)
- Complete response rate(CRR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(within 2 years after infusion)
- Duration of Response(DOR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.(within 2 years after infusion)
- Overall survival(OS) of administering CAR-NK-CD19 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