A Phase I/II Study Evaluating the Safety and the Efficacy of Human T Lymphoid Progenitor (HTLP) Injection to Accelerate Immune Reconstitution After Umbilical Cord Blood (UCB) Transplantation in Adult Patients With Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 10
- 试验地点
- 9
- 主要终点
- Cumulative incidence of grade III-IV graft-versus-host disease (GvHD)
研究概览
简要总结
This is an open-labelled and non-controlled Phase I/II clinical trial, evaluating the safety and the efficacy of Human T Lymphoid Progenitor (HTLP) injection to accelerate immune reconstitution after umbilical cord blood (UCB) transplantation in adult patients with hematologic malignancies. The dose limiting toxicity of HTLP injection will be evaluated using a model-based design.
详细描述
Allogeneic bone marrow transplantation (AlloSCT) is the treatment of choice for high- risk acute myeloid leukemias in complete first remission after induction therapy and other high-risk hematological malignancies. Umbilical cord blood grafts are frequently used for patients lacking an HLA- matched family donor (Matched-sibling donor, MSD) as well as in the absence of an appropriate unrelated donor (10/10 MUD). As any HSCT, UCB transplantations are associated with the risk of acute and chronic GVHD, post- transplant immunodeficiency with increased risk of infections as well as relapse. Especially the risk of infection and therefore non- relapse mortality (NRM) or transplant- related mortality (TRM) is significantly higher in UCB transplantations as compared to MSD or 10/10 MUD transplantations. All of these risks have been linked to a significant delay in immune reconstitution including various immune cell populations like CD4 and CD8 T cells, Treg, NK, iNKT, pDC and others.
The investigators therefore make the hypothesis that if T-cell-mediated immunity was rapidly generated after a partially HLA-compatible UCB transplantation will reduce the risk of infection and to prevent relapse without increasing the risk of GVHD.
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 66 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients (≥ 18 years old and <66 years old) at the time of inclusion and eligible for an allogeneic stem cells transplantation and fit to receive the specified conditioning regimen
- •Patients with hematologic malignancies
- •Absence of a matched - related sibling donor (MSD) or a matched unrelated donor (MUD) 10/10
- •Presence of two UCB units with the following criteria*: HLA- matched 4/8, 5/8, 6/8, 7/8 or 8/8 for HLA- A, -B, -C and DRB1 loci
- •Presence of at least one UCB unit with the following criteria*: ≥ 3 x 10e7 TNC/kg or ≥ 1.5 10e5 CD34+/kg pre- freezing
- •* For the UCB taken into HTLP culture, the CD34+ content does not need to meet the above cellularity criteria, as expansion during HTLP culture has been proven to ensure the appropriate number of CD7+ needed for each dose.
- •The non- cultured UCB will be chosen to have a higher CD34+ cell content in order to enable long- term hematopoietic engraftment
- •Absence of Donor Specific Antibodies (DSA) with a MFI > 5000
- •Patient affiliated to social security
- •Written, informed consent of the patient
排除标准
- •Any of the standard contraindications to allogeneic transplant
- •Left ventricular ejection fraction <50%
- •Abnormal biochemistry results (ALT/AST>10xULN, total bilirubin>2.5xULN, creatinin clearance <60ml/min)
- •Inability to understand and provide informed consent
- •Concomitant infectious disease: HTLV-I, HIV-I or HIV-II
- •Pregnancy or breastfeeding for women of childbearing potential
- •Patients with progressive hematologic malignancies
- •Previous participation within one month before inclusion in another protocol in which drugs may influence immune reconstitution of bone marrow transplantation
研究组 & 干预措施
Human T Lymphoid Progenitor (HTLP) injection
HTLP cellular product obtained after 7 days of culture of immune-selected CB
干预措施: Human T Lymphoid Progenitor (HTLP) injection (Drug)
结局指标
主要结局
Cumulative incidence of grade III-IV graft-versus-host disease (GvHD)
时间窗: Within 100 Days following HSCT
according to Glucksberg grading system, to define toxicity
CD4 + T cells analysis
时间窗: Within 100 days following HSCT
Efficacy defined by the presence of \>50/μl CD4+ CD3+ TCRαβ+ T cells at 2 consecutive measures \< within 4 months post HSCT.
次要结局
- Time to hematologic engraftment(Up to 24 months post-transplantation)
- Last transfusion of platelets and red blood cell(During the follow-up)
- Absolute numbers of neutrophils(Month 1, 2, 3, 6 and 12 post -transplantation)
- Time course of T cell immune reconstitution(Month 1, 2, 3, 6 and 12 post -transplantation)
- Immune phenotype (flow-cytometry analysis) of the different TCRαβ+ cell subpopulations(Month 1, 2, 3, 6 and 12 post -transplantation)
- B-cell reconstitution(Month 1, 2, 3, 6 and 12 post -transplantation)
- Reconstitution of the NK cell(Month 1, 2, 3, 6 and 12 post -transplantation)
- Assessment of engraftment of each UCB unit over time by hematological monitoring and chimerism analysis(at 1, 2, 3, 6 and 12 months following HSCT.)
- Graft failure/rejection rate(at 3 months following HSCT)
- Cumulative incidence of infections(at 3, 6 and 12 months post- transplantation)
- Cumulative incidence of acute and chronic episodes of GVHD and their grade according to Glucksberg GvHD staging.(at 3, 6, 12 and 24 months post-transplantation)
- Relapse rate(2 years)
- Overall survival(2 years)
- Disease-free survival(2 years)
- Progression-free survival(2 years)