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
概览
- 阶段
- 1/2 期
- 状态
- 进行中（未招募）
- 发起方
- Ospedale San Raffaele S.r.l.
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Overall survival from Advanced Therapy Investigational Medicinal Product (ATIMP) injection
概览
简要总结
To evaluate the safety and tolerability of autologous CD34+ cell enriched fraction that contains HSPC transduced with lentiviral vector (LVV) encoding the IDUA gene in pediatric patients with MPS-IH following a myeloablative and lymphoablative conditioning regimen.
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Follow-up
- 盲法
- None
入排标准
- 年龄范围
- 0 years 至 17 years（0-17 Years）
- 接受健康志愿者
- 是
入选标准
- •Written informed consent by parent/legal guardian
- •Sex: Males and Females
- •≥ 28 days and ≤ 11 years old
- •Biochemically and molecularly proven MPS-IH
- •Lansky Index > 80 %
- •Indication to HSCT
- •Lack of a non-heterozygous (for mutated IDUA) human leukocyte antigens (HLA) -matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5x10^7 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)
- •Controindications to Products equivalent to the IMP (PeIMP): G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab
- •Severe, active viral, bacterial, or fungal infection at eligibility evaluation
- •Patients affected by malignant 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 (also referred as, “cognitive standard score”, measured using Cognitive Scale for Bayley Scale of Infant Development and Performance IQ for WPPSI and WISC)
- •Previous allogeneic HSCT or gene therapy with a different product
结局指标
主要结局
Overall survival from Advanced Therapy Investigational Medicinal Product (ATIMP) injection
Overall survival from Advanced Therapy Investigational Medicinal Product (ATIMP) injection
Achievement of hematological engraftment less than or equal to day +45 from Advanced Therapy Investigational Medicinal Product (ATIMP) injection. Hematologic engraftment is defined as the first of 3 consecutive days with neutrophil count > 500/mm3 and platelets > 20,000/mm3 (in the absence of platelet transfusion for seven consecutive days).
Achievement of hematological engraftment less than or equal to day +45 from Advanced Therapy Investigational Medicinal Product (ATIMP) injection. Hematologic engraftment is defined as the first of 3 consecutive days with neutrophil count > 500/mm3 and platelets > 20,000/mm3 (in the absence of platelet transfusion for seven consecutive days).
Safety of the administration of autologous HSPC transduced with LVV-IDUA. This will be measured as: a) short-term tolerability (0-24 hours from ATIMP injection); b) absence of Replication Competent Lentivirus (RCL) (0-8 years); c) absence of malignancy or abnormal clonal proliferation due to insertional mutagenesis (0-8 years).
Safety of the administration of autologous HSPC transduced with LVV-IDUA. This will be measured as: a) short-term tolerability (0-24 hours from ATIMP injection); b) absence of Replication Competent Lentivirus (RCL) (0-8 years); c) absence of malignancy or abnormal clonal proliferation due to insertional mutagenesis (0-8 years).
Overall safety and tolerability measured by Adverse Event (AE) recording.
Overall safety and tolerability measured by Adverse Event (AE) recording.
IDUA activity in blood (dried blood spot, DBS) (up to supraphysiologic levels) at 1-year posttreatment
IDUA activity in blood (dried blood spot, DBS) (up to supraphysiologic levels) at 1-year posttreatment
次要结局
- Achievement of supraphysiologic IDUA activity in blood (DBS)
- IDUA activity in plasma
- Engraftment of transduced cells >= 0.30 vector copy number (VCN)/genome
- Normalization of urinary GAGs
- Normalization of spleen and liver (for age)
- Growth velocity treatment
- Anti-IDUA antibody immune response before and after infusion of IDUA LVV-transduced cells
研究者
Clinical
Scientific
Orchard Therapeutics (Europe) Limited