A Phase I-II Pilot Clinical Trial of Safety and Efficacy of Personalized Targeted Preparative Regimen With Allogeneic TcRαβ/CD19-depleted Hematopoietic Stem Cell Transplantation and Posttransplant Donor T- Cells Infusion in Children With Chemoresistаnt Acute Leukemia.
试验速览
- 阶段
- 3 期
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT
研究概览
简要总结
The purpose of this study is to evaluate the safety and efficiency of personalized targeted therapy in combination with high-dose chemotherapy as part of a preparative regimen before T-depleted allogeneic hematopoietic stem cell transplantation in children with chemoresistant acute leukemias
详细描述
The outcome of hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory leukemia is poor. The incidence of relapse exceeds 50% and survival varies from 10 to 40%. Additional attempts at remission induction with various combinations of chemotherapy are unlikely to improve the outcome and will contribute to toxicity.
The hypothesis of the study is that personalized targeted therapy combined with high-dose chemotherapy may improve the outcome of allogeneic HSCT in a cohort of pediatric patients with refractory leukemia.
Bcl-2, CD38, CD184 were chosen as potential targets due to frequent expression in pediatric acute leukemias, availability of marketed targeted therapies venetoclax, daratumumab and prelixafor, and expected non-overlapping toxicity profile of these agents and the conditioning regimen.
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
- — 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ability to give informed consent (for patients > 14 years old). For subjects < 18 years old their legal guardian must give informed consent
- •Disease stage
- •Acute myeloid leukemia (AML), relapsed or refractory, failure to achieve hematologic remission after at least to courses of intensive chemotherapy, including at least one course with high-dose AraC and fludarabine
- •Acute lymphoblastic leukemia (ALL), relapsed or refractory, failure to achieve hematologic remission after at least two high-dose therapy blocks
- •Patient eligible for current hematopoietic stem cell transplantation protocol
- •The BCL-2 expression must be detected on greater than 30% of tumor cells (AML and ALL) by flow cytometry
- •CD38 expression must be detected on greater than 30% of tumor cells (AML and ALL) by flow cytometry
- •Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.
- •Patient Clinical Performance Status: Karnofsky >50% or Lansky >50%
- •Patient Life Expectancy >12 weeks
- •Patients who agree to long-term follow up for up to 5 years
排除标准
- •Age >25 years
- •Patients with uncontrolled infections
- •Clearance of creatinine < 70 ml/min
- •Cardiac ejection fraction < 40%
- •Patients who can perform pulmonary function tests will be excluded if they have a diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) of < 50% predicted; patients who are unable to perform pulmonary function tests will be excluded if the oxygen (O2) saturation is < 92% on room air
- •Patients who have liver function test (LFTs) (including total bilirubin, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) >= twice the upper limit of normal
- •Karnofsky/Lansky Scale <70%
研究组 & 干预措施
intervention/treatment
Preparative chemotherapy before allogeneic HSCT
- Fludarabin
- Cytarabine
- Venetoclax
- Daratumomab
- Vecanoid
- treosulfan
- fludarabine
- thiophosphomide
- Venetoclax
- Plerixafor
- abatacept
- tocilizumab
- rituximab
- HSCT from the haploidentical donor, ex vivo depleted of alpha/beta T lymphocytes
干预措施: Preparative regimen (Drug)
结局指标
主要结局
cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT
时间窗: 30 days after HSCT
Overall response rate
时间窗: 30 days after HSCT
Proportion of patients with hematologic remission at time points
Partial response rate
时间窗: 30 days after HSCT
Proportion of patients with MRD negativity at time points
Rate of toxicity stage > 3 according to CTCAE 5.0
时间窗: 40 days after first drug administration
Proportion of patients with allergic/ anaphylaxis reaction toxicity stage \> 3 according to CTCAE 5.0
cumulative incidence of transplant-related mortality
时间窗: 100 days after HSCT
次要结局
- Rate of expression of target molecule on blast cells(1 week before first drug administration)
- cumulative incidence of acute GVHD grade II-IV(120 days after HSCT)
- cumulative incidence of chronic GvHD(1 year after HSCT)
- Rate of immune recovery at day 30(30)
- overall survival(1 year after HSCT)
- event-free survival(1 year after HSCT)