A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 16
- 主要终点
- Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 and Without Allo-HSCT or Rescue Cell Administration
研究概览
简要总结
This trial assessed the efficacy and safety of autologous cluster of differentiation 34 (CD34+) hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector (also called elivaldogene autotemcel or eli-cel), for the treatment of cerebral adrenoleukodystrophy (CALD). A participant's blood stem cells were collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. After modification (transduction) with the Lenti-D lentiviral vector, the cells were transplanted back into the participant following myeloablative conditioning. Participants in this study will be continuously followed in study LTF-304.
详细描述
For study ALD-102 the Transplant Population (TP), Neutrophil Engraftment Population (NEP), and Intent-to-Treat Population (ITT) were identical.
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
- — 至 17 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Informed consent was obtained from a competent custodial parent or guardian with legal capacity to execute a local institutional review board (IRB)/Independent Ethics Committee (IEC) approved consent (informed assent will be sought from capable participants, in accordance with the directive of the IRB/IEC and with local requirements).
- •Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, participant assent.
- •Active cerebral adrenoleukodystrophy (ALD) as defined by:
- •Elevated very long chain fatty acids (VLCFA) values, and
- •Active CNS disease established by central radiographic review of brain magnetic resonance imaging (MRI) demonstrating:
- •Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and
- •Gadolinium enhancement on MRI of demyelinating lesions.
- •NFS less than or equal to (<or=) 1.
排除标准
- •Receipt of an allogeneic transplant or gene therapy.
- •Availability of a willing 10/10 HLA-matched sibling donor (excluding female heterozygotes).
- •Use of statins, Lorenzo's Oil, or dietary regimens used to lower very long chain fatty acids (VLCFA) levels. Note: participants must discontinue use of these medications at time of consent.
- •Receipt of an investigational study drug or procedure within 3 months before Screening that might confound study outcomes. Use of investigational study drugs is prohibited throughout the course of the study.
- •Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents).
- •Hematological compromise as evidenced by:
- •Peripheral blood absolute neutrophil count (ANC) count < 1500 cells/ cubic milli meter (mm3),
- •Platelet count < 100,000 cells/mm3, or
- •Hemoglobin < 10 gram per deciliter (g/dL).
- •Uncorrected bleeding disorder.
- •Hepatic compromise as evidenced by:
- •Aspartate transaminase (AST) value > 2.5×upper limit of normal (ULN)
- •Alanine transaminase (ALT) value > 2.5×ULN
- •Total bilirubin value > 3.0 milligram per deciliter (mg/dL), except if there is a diagnosis of Gilbert's Syndrome and the participant is otherwise stable
- •Renal compromise as evidenced by abnormal renal function (actual or calculated creatinine clearance < 50 milliliter per minute [mL/min])
- •Cardiac compromise as evidenced by left ventricular ejection fraction <40 percent (%)
- •Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis).
- •Clinically significant active bacterial, viral, fungal, parasitic, or prion-associated infection
- •Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B; hepatitis C; human T lymphotrophic virus 1 (HTLV-1). (Note that participants who have been vaccinated against hepatitis B [hepatitis B surface antibody-positive] who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B core antibody (Ab)] are eligible. Participants with past exposure to hepatitis B virus (HBV [HBcAb positive and/or HBeAb positive]) are also eligible for the study provided they have a negative test for HBV DNA. Also note that participants who are positive for anti-hepatitis C antibody are eligible as long as they have a negative hepatitis C viral load.
- •Any clinically significant cardiovascular or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures.
- •Absence of adequate contraception for fertile participants. Male participants and their female partners are required to use two different effective methods of contraception from Screening through at least 6 months after drug product infusion. If subjects are truly sexually abstinent (where true sexual abstinence is defined as being in line with the preferred and usual lifestyle of the subject), no second method is required.
- •Any contraindications to the use of granulocyte colony stimulating (G-CSF) during the mobilization of HSCs, and any contraindications to the use of busulfan or cyclophosphamide, including known hypersensitivity to the active substances or to any of the excipients in their formulations.
结局指标
主要结局
Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 and Without Allo-HSCT or Rescue Cell Administration
时间窗: At Month 24
The 6 MFDs consisted of loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement. Month 24 MFD-Free survival criteria was defined as: alive at 24 months post-infusion; had not developed any of the MFDs by 24 months post-infusion; had not received rescue cell administration or allo-HSCT by 24 months post-infusion; and had not withdrawn from the study or had not been lost to follow-up by 24 months post-infusion. Percentage of participants who were alive and have none of the 6 major functional disabilities (MFDs) at Month 24 were reported.
Proportion of Participants Who Had Experienced Either Acute ([>or=] Grade II) or Chronic Graft Versus Host Disease (GVHD) by Month 24
时间窗: By Month 24
Acute GVHD graded on the Acute GVHD Grading Scale (I-IV): Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening; chronic GVHD was determined by the Investigator. Percentage of participants who experienced with either acute (\>= Grade II) or chronic GVHD at Month 24 were reported.
次要结局
- Major Functional Disability (MFD)-Free Survival Rate(At 24 months after Lenti-D drug infusion)
- Percentage of Participants Who Demonstrated Resolution of Gadolinium Positivity on Magnetic Resonance Imaging (MRI) at Month 24(At Month 24)
- Time to Sustained Resolution of Gadolinium Positivity on MRI(Up to Month 24)
- Number of Participants With Change in Total Neurologic Function Score (NFS) From Baseline up to Month 24(Baseline up to Month 24)
- Proportion of Participants With Neutrophil Engraftment by 42 Days Post-drug Product Infusion(By 42 days post-drug infusion)
- Time to Neutrophil Engraftment Post-drug Product Infusion(By 42 days post-drug infusion)
- Number of Emergency Room Visits (Post-Neutrophil Engraftment) By Month 24(From Post-Neutrophil Engraftment up to Month 24)
- Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) By Month 24(From post-neutrophil engraftment up to Month 24)
- Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) By Month 24(From post-neutrophil engraftment up to Month 24)
- Number of Participants With Vector-Derived Replication Competent Lentivirus (RCL) Detected by Month 24(By Month 24)
- Overall Survival Rate(At 24 months after Lenti-D drug infusion)
- Proportion of Participants With Engraftment Failure By Month 24(By Month 24)
- Duration of ICU Stays (Post-neutrophil Engraftment) By Month 24(From post-neutrophil engraftment up to Month 24)
- Number of Participants With Insertional Oncogenesis By Month 24(By Month 24)
- Proportion of Participants With Platelet Engraftment by Month 24(By Month 24)
- Time to Platelet Engraftment Post-drug Product Infusion(By Month 24)
- Proportion of Participants Who Underwent a Subsequent Allo-Hematopoietic Stem Cell (HSC) Infusion by Month 24(By Month 24)
- Percentage of Participants With Potentially Clinical Significant Changes in Laboratory Parameters by Month 24(From time of drug product infusion up to Month 24)
- Percentage of Participants With Transplant-related Mortality Through 100 and 365 Days Post-drug Product Infusion(From time of drug product infusion through 100 and 365 days post-drug product infusion)
- Percentage of Participants With Adverse Events (AEs), Serious AEs, Grade >=3 AE, Related AEs, Related SAEs and Related Grade >=3 AEs(From date of informed consent up to Month 24)
- Duration of In-patient Hospitalizations (Post-Neutrophil Engraftment) up to Month 24(From post-neutrophil engraftment up to Month 24)