Safety and Efficacy of Anti-CD123 Chimeric Antigen Receptor-Modified Autologous T Cells (CART123) in Patients With Relapsed/Refractory CD123+ Hematologic Malignancies: A Dose Escalation, Open-Label, Phase I Study
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 18
- 试验地点
- 2
- 主要终点
- Safety and tolerability of autologous CART123 cells
研究概览
简要总结
Adult patients with refractory or relapsed CD123+ hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or blastic plasmocytoid dentritic cell neoplasm will be recruited in the trial. CART123 cells will be manufatured from blood of each patient. During the production of CAR123 cells, patients may receive appropriate bridging therapy. After cells are produced, participants will undergo a single course of lymphodepleting chemotherapy and receive a single dose of CAR123 T cells. The trial will establish the recommended dose for further studies, either the Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD). Patients must be eligible for hematopoietic stem cell transplantation in order to participate in the trial.
详细描述
This is an open-label, single arm study on up to 18 adult subjects with refractory or relapsed CD123+ AML, MDS, ALL or BPDCN. Following lymphodepleting conditioning regimen, the subjects will receive a single dose of autologous CAR123 T lymphocytes supplied by the sponsor´s manufacturing facility.
CART123 dose will be increased in three predefined steps using the accelerated Bayesian optimal interval (BOIN) design in order to establish recommended CART123 dose for further study, which will be either Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD), whichever is reached first.
Alternative dosing schedule will be adopted in case of dose limitation due to insufficient CART123 expansion during IMP manufacture.
Due to concern for potentially prolonged or irreversible hematologic toxicity of CART123, all patients recruited in the study must be eligible for hematopoietic stem cell transplantation (HSCT) and have a donor of allogeneic hematopoietic stem cells identified and cleared by the transplant center. Decision to perform HSCT will be made on a case-by-case basis.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with AML, MDS-IB2, BPDCN or ALL positive for CD123 antigen, who meet one of disease specific criteria below:
- •a) Patients with AML will be eligible if they meet one of the following criteria:
- •i) Patient with refractory AML defined as failure to achieve CR or CRi after at least 2 cycles of induction chemotherapy or 1 cycle of high dose salvage regimen or 4 cycles of venetoclax with azacytidine OR
- •ii) Second or subsequent relapse of AML OR
- •iii) Relapse after allogeneic HSCT.
- •b) Patients with ALL will be eligible if they meet one of following criteria:
- •i) disease refractory to or relapsed after CAR-19 cell therapy OR
- •ii) CD19 negative relapse ineligible for treatment with TKI inhibitors and inotuzumab ozogamicin.
- •c) Patients with BPDCN will be eligible if they meet following criteria:
- •i) Refractory or relapsing after chemotherapy with or without allogeneic stem cell transplantation.
- •d) Patients with MDS-IB2 will be eligible if they meet one of following criteria:
- •i) Disease refractory to at least four cycles of azacytidine or progression on azacytidine-based therapy OR
- •ii) Disease refractory to induction chemotherapy OR
- •iii) Relapse after haematopoietic stem cell transplantation.
- •CD123 expression on malignant cells confirmed by flow cytometry or by immunohistochemistry.
- •Age between 18 and 70 years.
- •Patient has a suitable donor for allogeneic hematopoietic stem cell transplantation. Workup and clearance of the donor must be completed before IMP administration.
- •Patient able to understand and sign informed consent.
- •Women of child-bearing potential: negative pregnancy test at enrolment (PSV) and at Visit
- •Patient for whom there are no standard-of-care treatments available or such treatment options have been exhausted.
排除标准
- •Known hypersensitivity to any component of the IMP.
- •Allogeneic HSCT within 3 months prior to IMP administration.
- •Severe, uncontrolled active infection.
- •Life expectancy < 8 weeks.
- •Respiratory insufficiency (need for oxygen therapy).
- •Significant liver impairment: bilirubin > 50 µmol/L, AST or ALT > 4 times normal upper limit.
- •Acute kidney injury with serum creatinine > 180 µmol/L, oliguria or need for acute dialysis.
- •Heart failure with LVEF < 50% by echocardiography.
- •Presence of active grade 3 - 4 acute GvHD or severe chronic GvHD.
- •Serious uncontrolled neurological comorbidity.
- •Vaccination with live virus vaccines in the 4 weeks before IMP administration and within 90 days after the IMP dose.
- •Women: pregnancy or breast-feeding.
- •Subjects of fertile age, unless permanent sexual abstinence is their lifestyle choice:
- •female patients of childbearing potential not willing to use a highly effective method of contraception during the study,
- •male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a highly effective method of contraception during the study.
研究组 & 干预措施
Treatment Arm
Experimental: Autologous CAR123 T lymphocytes
干预措施: Autologous CAR123 T lymphocytes (Biological)
结局指标
主要结局
Safety and tolerability of autologous CART123 cells
时间窗: 28 Days, Months 24
Cumulative incidence of IMP-related adverse events (AEs) graded by ASTCT consensus grading criteria for Cytokine Release Syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) and by Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 for other AEs
Rate of hematological recovery
时间窗: 14 Days, 28 Days, 1Year, Months 12, Months 24
Rate of hematological recovery, defined as absolute neutrophil count (ANC) \> 1x 10\^9/L and platelet count \> 20x10\^9/L without transfusion support. Hematological recovery before and after HSCT will be evaluated separately.
A dose of CART123 cells for further study
时间窗: 14 Days, 28 Days, 1year, Months 12, Months 24
Incidence of dose-limiting toxicities (DLTs) and other safety data after IMP administration.
次要结局
- Morphologic Leukemia Free State (MLFS).(at day 14 and 28 after IMP administration.)
- Complete Remission (CR) rate(at 28 days and at any later point after IMP administration, before and after HSCT.)
- Median Overall Survival and Overall Survival(at one year after IMP administration.)
- Feasibility and need for allogeneic hematopoietic cell transplantation after IMP administration(within 28 days of IMP administration)