Phase I/II Study Evaluating Safety and Efficacy of Autologous Hematopoietic Stem and Progenitor Cells Genetically Modified With IDUA Lentiviral Vector Encoding for the Human α-L-iduronidase Gene for the Treatment of Patients Affected by Mucopolysaccharidosis Type I, Hurler Variant
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- Achievement of haematological engraftment
研究概览
简要总结
This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem and progenitor cells genetically modified with IDUA lentiviral vector encoding for the human α-L-iduronidase gene for the treatment of patients affected by Mucopolysaccharidosis Type I, Hurler variant
详细描述
Pediatric patients with mucopolysaccharidosis type I will be treated with genetically modified autologous hematopoietic stem cells collected from mobilized peripheral blood (or bone marrow if mobilization is not feasible) and transduced with IDUA lentiviral vector encoding for the human α-L-iduronidase gene.
Participants will be followed for up to 15 years post treatment (per regulatory guidelines for follow up of patients treated with ATMPs, under this study (TigetT10_MPSIH) or via enrollment into a separate long term follow-up (LTFU) study for the overall OTL-203 Clinical Development Program, if one is set up prior to their Year 15 visit.
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
- 28 Days 至 11 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent by parent/legal guardian
- •Sex: Males and Females
- •Age: ≥ 28 days and ≤ 11 years old
- •Biochemically and molecularly proven MPS IH
- •Lansky index >80%
- •Indication to hematopoietic stem cell transplant
- •Lack of a non-heterozygous (for mutated IDUA) HLA-matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5 x 10^7 Total Nucleated Cells (TNC)/Kg after 1-month search.(This criterion will not apply to patients whose country of origin does not offer unrelated donor cord blood transplantation).
- •Adequate cardiac, renal, hepatic and pulmonary functions
排除标准
- •Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
- •Severe, active viral, bacterial or fungal infection at eligibility evaluation
- •Patients affected by neoplasia or family history of familial cancer syndromes
- •Cytogenetic alterations associated with high risk of developing hematological malignancies
- •History of uncontrolled seizures
- •Patients with end-organ damage or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
- •Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or Treponema Pallidum or Mycoplasma active infection
- •Patients with DQ/IQ <70
- •Previous allogeneic hematopoietic stem cells transplantation or gene therapy with a different product
- •Contraindications to PeIMP (G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab)
结局指标
主要结局
Achievement of haematological engraftment
时间窗: within day +45 after gene therapy
Percentage of subjects with both neutrophil count more than 500/mm3 and platelets more than 20,000/mm3 (in the absence of platelet transfusion for seven consecutive days) on 3 consecutive blood counts in the first 45 days from ATIMP injection.
Overall survival
时间窗: Assessed at multiple timepoints up to 15 years post-treatment
Number and percentage of subjects alive at the end of the trial
Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Short term tolerability
时间窗: 0-24 hours from ATIMP injection
Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions
Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Absence of Replication Competent Lentivirus
时间窗: Assessed at multiple timepoints up to 8 years post-treatment, or if clinically indicated
Percentage of subjects without Replication Competent Lentivirus
Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Absence of malignancy or abnormal clonal proliferation
时间窗: Assessed at multiple timepoints up to 15 years post-treatment
Percentage of subjects without abnormal clonal proliferation
Overall safety and tolerability (AE)
时间窗: Assessed at multiple timepoints up to 15 years post-treatment
The number of AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) and the percentage of subjects experiencing AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) will be summarized by severity and within body system involved. Narratives will also be presented. The rate of occurrence of these events will also be estimated.
IDUA activity in blood (up to supraphysiologic levels) at 1-year post-treatment
时间窗: At 1 year post-treatment
IDUA activity measured on peripheral dried blood spot
Overall survival
时间窗: 8 years
Number and percentage of subjects alive at the end of the trial
Achievement of haematological engraftment
时间窗: within day +45 after gene therapy
Percentage of subjects with both neutrophil count more than 500/mm3 and platelets more than 20,000/mm3 (in the absence of platelet transfusion for seven consecutive days) on 3 consecutive blood counts in the first 45 days from ATIMP injection.
Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability
时间窗: 0-24 hours from ATIMP injection
Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions
Overall safety and tolerability (AE)
时间窗: Assessed at multiple timepoints up to 8 years post-treatment
The number of AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) and the percentage of subjects experiencing AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) will be summarized by severity and within body system involved. Narratives will also be presented. The rate of occurrence of these events will also be estimated.
IDUA activity in blood (up to supraphysiologic levels) at 1-year post-treatment
时间窗: Assessed at multiple timepoints up to 8 years post-treatment
IDUA activity measured on peripheral blood dried spot
Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus
时间窗: Assessed at multiple timepoints up to 8 years post-treatment
Percentage of subjects without Replication Competent Lentivirus
Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation
时间窗: Assessed at multiple timepoints up to 8 years post-treatment
Percentage of subjects without abnormal clonal proliferation
次要结局
- Anti-IDUA antibody immune response(Assessed at multiple timepoints up to 8 years post-treatment, or if clinically indicated)
- Achievement of supraphysiologic IDUA activity in blood(Assessed at multiple timepoints up to 15 years post-treatment)
- IDUA activity in plasma(Assessed at multiple timepoints up to 15 years post-treatment)
- Engraftment of transduced cells ≥ 0.30 VCN/genome(Assessed at multiple timepoints up to 15 years post-treatment)
- Normalization of urinary GAGs(Assessed at multiple timepoints up to 15 years post-treatment)
- Normalization of spleen and liver(Assessed at multiple timepoints up to 15 years post-treatment)
- Growth velocity(Assessed at multiple timepoints up to 15 years post-treatment)
- Anti-IDUA antibody immune response(Assessed at multiple timepoints up to 8 years post-treatment)
- Achievement of supraphysiologic IDUA activity in blood(Assessed at multiple timepoints up to 8 years post-treatment)
- Growth velocity(Assessed at multiple timepoints up to 8 years post-treatment)
- IDUA activity in plasma(Assessed at multiple timepoints up to 8 years post-treatment)
- Engraftment of transduced cells ≥ 0.30 VCN/genome(Assessed at multiple timepoints up to 8 years post-treatment)
- Normalization of urinary GAGs(Assessed at multiple timepoints up to 8 years post-treatment)
- Normalization of spleen and liver(Assessed at multiple timepoints up to 8 years post-treatment)