Phase I/II Clinical Trial of mbIL21 ex Vivo-expanded Donor-derived NK-cell Infusions With Hematopoietic Stem Cell Transplantation for Disease Relapse Prophylaxis in Pediatric and Young Adult Patients With Chemorefractory or Minimal Residual Disease Positive Acute Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Proportion of patients who received the planned dose of NK cells without adverse reactions grade ≥3 according to CTCAE v5.0
研究概览
简要总结
This pilot clinical trial aims to evaluate the feasibility, adverse reactions and maximum tolerated dose of mbIL21 ex vivo-expanded donor-derived NK-cell infusions before and after haploidentical or matched-related hematopoietic stem cell transplantation in a cohort of pediatric and young adult patients with chemorefractory or minimal residual disease (MRD) positive acute leukemia.
详细描述
Rationale. In the context of treating children and young adults with high-risk or chemorefractory acute leukemia allogeneic hematopoietic stem cell transplantation (allo-HSCT) plays a crucial role. It is well known, that residual tumor cell volume at the time of allo-HSCT has a significant impact on its outcomes. The antileukemic effect of allo-HSCT in some hematologic malignancies is predominantly mediated by graft-versus-leukemia effect, which is an immune-mediated reaction of engrafted donor hematopoiesis against the recipient's tumor cells. The graft-versus-leukemia effect is generally ascribed to NK-cells conserved within the graft or arising from it early after transplantation.
Primary objective: to evaluate feasibility, safety and to identify the maximum tolerated dose (MTD) of mbIL21 ex vivo-expanded donor-derived NK-cell cells to be infused to children and young adults aged 1 to 25 years with chemorefractory or pre-transplant MRD-positive acute leukemia undergoing allo-HSCT.
Secondary objectives:
- To assess the short-term disease response to NK cell infusions as an adjunct to allo-HSCT.
- To assess the impact of NK cell infusions on reconstitution of main lymphocyte subpopulations in allo-HSCT recipients.
- To assess the impact of NK cell infusions on main allo-HSCT outcomes. Outline. This is a phase I, 3+3 dose-escalation study of NK-cells followed by a phase II study. Conditioning regimen will be split into two parts. Two donor NK-cell infusions will be carried out: after the first part of conditioning and early after transplant.
FIRST PART OF CONDITIONING: Patients receive fludarabine 40 mg/m2/day IV over 1 hour on days -14 and -13, thiotepa 10 mg/kg/course IV over 1 hour on days -14 and -13 and cyclophosphamide 500 mg/m2 IV over 1 hour on day -14.
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
- 1 Month 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient (age from 14 to 25 years) and/or patient's legal representative (age from 0 to 18 years) should provide written informed consent.
- •Patients with one of the following disease:
- •Acute myeloid leukemia: a. primary refractory disease (absence of complete remission (CR) after two induction regimens), b. refractory relapse (absence of CR after one salvage regimen), c. MRD-persistence before conditioning (presence of residual leukemic population more than 0,01% of bone marrow nucleated cells by flow cytometry);
- •Acute T-lymphoblastic leukemia: a. primary refractory disease (absence of complete remission (CR) after two induction regimens), b. refractory relapse (absence of CR after one salvage regimen), c. MRD-persistence before conditioning (presence of residual leukemic population more than 0,1% of bone marrow nucleated cells by flow cytometry);
- •Acute mixed phenotype leukemia: a. primary refractory disease (absence of complete remission (CR) after two induction regimens), b. refractory relapse (absence of CR after one salvage regimen), c. MRD-persistence before conditioning (presence of residual leukemic population more than 0,01% of bone marrow nucleated cells by flow cytometry).
- •Patient is indicated to receive allo-HSCT according to actual clinical practice.
- •Haploidentical or matched related donor was chosen and is available for allo-HSCT (and NK-cell therapy).
- •Patient's clinical status: Lansky/Karnowski index ≥50%.
- •Kidney function: clearance of endogenous creatinine or glomerular filtration rate according to Schwarz equation ≥50 ml/min/1,73 m
- •Liver function: total bilirubin ≤3 ULN except for Gilbert's disease, ALT/AST ≤3 ULN.
- •Heart function: left ventricular ejection fraction ≥40%.
- •Lung function: lung capacity ≥50%, for children who cannot carry out of respiratory function - oxygen saturation during pulse oximetry ≥92% (without supplemental oxygen).
- •Life expectancy ≥8 weeks.
- •Patients who agree to long-term follow up for up to 2 years.
排除标准
- •Inability to provide or withdrawal of written informed consent.
- •Cellular therapy including allo-HSCT within prior 4 months period, absence of active signs of GVHD, sinusoidal obstruction syndrome, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome.
- •Active hepatitis B, C or HIV infection.
- •Pregnant or lactating women.
- •Uncontrolled infection; principal investigator is the final arbiter of this criterion.
- •Clinical signs of grade ≥3 CNS disorders (seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, organic brain syndrome, psychosis, coordination or movement disorder).
- •Mental illness of the patient or caregivers, making it impossible to realize the essence of the study and compromising compliance with medical appointments and sanitary and hygienic regime.
研究组 & 干预措施
Biological: Donor-derived Natural Killer Cell Infusions
干预措施: Donor-derived Natural Killer Cell (Biological)
结局指标
主要结局
Proportion of patients who received the planned dose of NK cells without adverse reactions grade ≥3 according to CTCAE v5.0
时间窗: 180 days from the last administration of donor NK cells
次要结局
- Rate of morphologic bone marrow leukemia-free state(on day -4 before HSCT, and +30 days after HSCT)
- Rate of MRD-negativity(on days -4 before HSCT and +30 days after HSCT)
- Cumulative incidence of developing acute graft-versus-host disease(180 days from the last administration of donor NK cells)
- Cumulative incidence of relapse(2 years after allo-HSCT)
- Cumulative incidence of transplantation-related mortality(100 days and 2 years after allo-HSCT)
- Probability of engraftment(30 days after allo-HSCT)
- Overall survival(2 years after allo-HSCT)