Phase I/II Clinical Trial of Autologous Hematopoietic Stem Cell Gene Therapy in RAG1-Deficient Severe Combined Immunodeficiency
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 发起方
- 入组人数
- 10
- 试验地点
- 10
- 主要终点
- Feasibility of successful generation of RAG1 LV CD34+ cells
研究概览
简要总结
This trial is a prospective, non-randomized, open-label, multicentre single-arm phase I/II intervention trial in children up to 24 months of age with RAG1-deficient SCID and an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. The trial involves infusion of autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (hereafter called RAG1 LV CD34+ cells) in up to 10 patients with RAG1-deficient SCID. Patients will be regularly monitored for 5 years after infusion. Follow up as part of routine clinical care for post-transplant patients will be annual after this, for at least 15 years after IMP infusion.
详细描述
Severe combined immunodeficiency (SCID) is a genetically heterogeneous life-threatening disease characterized by severely impaired T cell development with or without impaired natural killer (NK) and B cell development or function depending on the genetic defect. Mutations in recombination activating genes 1 and 2 (RAG1 and RAG2) represent about 20% of all types of SCID. SCID is a paediatric emergency since it leads to severe, life-threatening and recurrent infections often in combination with protracted diarrhoea and failure to thrive. When left untreated, it is usually fatal within the first year of life. Currently, the only curative treatment option for RAG-deficient SCID is allogeneic hematopoietic stem cell transplantation (HSCT). Despite improvements in HSCT in recent years, this treatment is associated with serious potential complications like graft-versus-host disease which results in an unfavourable outcome, particularly in patients who lack a human leukocyte antigen (HLA)-matched donor. In recent years, gene therapy based on transplantation of autologous gene-corrected hematopoietic stem cells (HSC) has evolved as an effective and safe therapeutic option for X-linked and ADA-deficient forms of SCID. We have recently demonstrated that gene therapy using lentiviral (LV) self-inactivating (SIN) vectors expressing codon-optimized human RAG1 in a mouse model for RAG1-deficient SCID effectively restores T and B cell development and function.
In this phase I/II intervention trial safety and efficacy of gene therapy using gene-corrected autologous CD34+-selected mobilized peripheral cells will be investigated in patients with RAG1-deficient SCID with an indication for allogeneic HSCT but lacking an HLA-identical sibling/ family donor.
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
- 8 Weeks 至 24 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •RAG1-deficient SCID as confirmed by genetic analysis
- •Peripheral blood CD3+T cells < 300/μL
- •Absence of peripheral blood naïve CD4+ T cells
- •Age < 2 years
- •Age at least 8 weeks by the time of busulfan and fludarabine administration
- •Lack of an available HLA-identical sibling/family donor
- •Signed informed consent (parental or guardian)
- •Able to return to the local HSCT centre for follow-up (per protocol) during the 5-year trial and up to at least 15-year long-term follow-up after IMP administration
排除标准
- •Omenn syndrome
- •Previous allogeneic HSCT
- •Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below):
- •Mechanical ventilation
- •Shortening fraction on echocardiogram <25%
- •Renal failure defined as dialysis dependence
- •Uncontrolled seizure disorder
- •Any other condition that the investigator considers is a contraindication to collection and/or infusion of trans-duced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication f to busulfan, major congenital abnormalities, ineligible to receive anaesthesia, or documented refusal or inability of the family to return for scheduled visits.
- •Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection
研究组 & 干预措施
Gene therapy
In this arm, 10 patients will be included for gene therarpy
干预措施: Gene therapy (Genetic)
结局指标
主要结局
Feasibility of successful generation of RAG1 LV CD34+ cells
时间窗: 2 years
IMP (RAG1 LV CD34+ cells) that meets the release criteria as defined in the IMPD.
Safety of RAG1 lentiviral gene therapy
时间窗: 2 years
Overall survival and event-free survival (EFS) after infusion of the IMP with events
To evaluate the effect of RAG1 gene therapy on overall survival.
时间窗: 5 years
Overall survival
To evaluate the efficacy of RAG1 gene therapy in achieving reconstitution of the T and B cell immune system in patients with RAG1-SCID at 6 months.
时间窗: 6 Months
Evaluation of immune reconstitution at Month 6 defined as * Presence of naive CD4+ T cells * Total CD3+ T-cells \> 300 cells/μL * Total CD4+ T-cells \> 200 cells/μL
To evaluate the safety and tolerability of the RAG1 gene therapy product, including identification of short- and long-term adverse events.
时间窗: 5 years
* Number of patients with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs, e.g. insertional mutagenesis) and relatedness of the events to intervention, treatment and/or investigational drug * Incidence of new or worsening abnormalities in laboratory safety parameters and clinical assessments (including hematology, biochemistry, endocrinology, physical examination findings, vital signs, cardiac ultrasound, and Lansky performance score).
次要结局
- Thymic function(1 year)
- T cell reconstitution(1 year)
- Immunoglobulin dependence(2 years)
- Persistence of gene marking(1 year)
- Occurrence of Infections(2 years)
- T and B cell receptor repertoire(1 year)
- Quality of life(2 years)
- Failure to thrive(2 years)
- To evaluate the effect of RAG1 gene therapy on event-free survival.(1 year)
- To evaluate the efficacy of RAG1 gene therapy in achieving independence of Immunoglobulin substitution(2 years)
- To evaluate the long-term efficacy of RAG1 gene therapy in reconstituting the immune system in patients with RAG1-SCID.(6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months)
- To evaluate the pharmacodynamic effects of RAG1 gene therapy.(6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months)
- To evaluate the effects of RAG1 gene therapy on quality of life(2 years)
- To evaluate the efficacy of RAG1 gene therapy in enabling a successful serologic response to vaccination(2 years)
研究者
alankester
Principal Investigator
Leiden University Medical Center