Last updated: 11/03/2018 23:32:15
This product has been transferred to Orchard Therapeutics Limited. GSK Clinical Study Register is no longer maintained for this study. The most up to date information is available on clinicaltrials.gov
A safety and efficacy study of cryopreserved GSK2696274 for treatment of metachromatic leukodystrophy (MLD)
GSK study ID
205756
Clinicaltrials.gov ID
EudraCT ID
EU CT Number
Not applicable
Trial status
No longer a GSK study
No longer a GSK study
Trial overview
Official title: A single arm, open label, clinical study of cryopreserved autologous CD34+ cells transduced with lentiviral vector containing human ARSA cDNA (GSK2696274), for the treatment of early onset Metachromatic Leukodystrophy (MLD)
Trial description: GSK2696274 is autologous cluster of differentiation 34+ (CD34+) cells transduced with lentiviral vector containing human arylsulfatase A (ARSA) complementary deoxyribonucleic acid (cDNA) used for the treatment of MLD. MLD is an autosomal recessive lysosomal storage disorder (LSD) characterized by severe and progressive demyelination affecting the central and peripheral nervous system. This study will assess safety and efficacy of treatment using cryopreserved formulation of GSK2696274 in pediatric subjects with pre-symptomatic Early Onset MLD (Late Infantile (LI) to Early Juvenile (EJ) MLD). Up to 10 subjects may be included in the study. A minimum of 3 subjects are planned to assess the primary endpoint. Subjects will be followed up for a minimum period of 8 years post treatment.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Not applicable
Primary outcomes:
Change in Gross Motor Function Measure (GMFM) score
Timeframe: At 24 months post gene-therapy
Secondary outcomes:
Change in Gross Motor Function Measure (GMFM) score
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in Gross Motor Function Classification (GMFC)-MLD score
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in neurological examinations
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in Nerve Conduction Velocity (NCV)
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in total score for brain magnetic resonance (MR) imaging
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in neurocognitive function (Intelligence Quotient [IQ])
Timeframe: At multiple visits up to 8 years post-gene therapy
Engraftment measured by percent Lentiviral (LV) positive clonogenic progenitors in bone marrow
Timeframe: At multiple visits up to 8 years post-gene therapy
Vector copy number (VCN) level in bone marrow mononuclear cells
Timeframe: At multiple visits up to 8 years post-gene therapy
VCN level in peripheral blood mononuclear cell (PBMCs)
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in ARSA activity in total PBMCs
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in ARSA activity in PB CD15+ cells
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in ARSA activity in PB CD14+ cells
Timeframe: At multiple visits up to 8 years post-gene therapy
Change in ARSA activity in cerebrospinal fluid (CSF)
Timeframe: At multiple visits up to 8 years post-gene therapy
Safety and tolerability as measured by recording of adverse events (AEs)
Timeframe: Up to 8 years post-gene therapy
Safety and tolerability as measured by number of subjects not achieving hematological recovery by Day 60 (i.e., engraftment failure)
Timeframe: By Day 60 post-gene therapy
Safety and tolerability as measured by number of subjects with incidences and titers of antibodies against ARSA
Timeframe: Up to 8 years post-gene therapy
Safety and tolerability as measured by number of subjects with abnormal clonal proliferation (ACP)
Timeframe: Up to 8 years post gene-therapy
Safety and tolerability as measured by number of subjects with replication competent lentivirus (RCL)
Timeframe: Up to 8 years post gene-therapy
Interventions:
Enrollment:
10
Primary completion date:
2022-22-08
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Not applicable
Medical condition
Lysosomal Storage Disease
Product
GSK2696274, busulfan
Collaborators
Ospedale (Hospital) San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
Study date(s)
December 2017 to August 2028
Type
Interventional
Phase
3
Participation criteria
Sex
Female & Male
Age
Not applicable
Accepts healthy volunteers
No
- Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles, either known or novel mutations. Novel mutations will be analyzed with in silico prediction tools and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.
- Eligible subjects must have EITHER
- Symptoms of MLD, defined as either of the following:
- a) delay in expected achievement of independent standing or independent walking, together with abnormal signs at neurological evaluation
Inclusion and exclusion criteria
Inclusion criteria:
- Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles, either known or novel mutations. Novel mutations will be analyzed with in silico prediction tools and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.
- Eligible subjects must have EITHER a) an older sibling affected by MLD (index case), whose age of symptom onset was <=6 years of age (i.e., had not celebrated 7th birthday). Subjects will be classified as LI, EJ or intermediate LI/EJ based on age of symptom onset in the index case and their ARSA genotype; LI: symptom onset in index case <=30 months of age and genotype typically 0/0; EJ: symptom onset in index case >30 months and <=6 years of age with genotype typically 0/R; Intermediate LI/EJ: symptom onset in index case <=6 years of age but unable to unambiguously characterize index case as LI or EJ OR b) if MLD is diagnosed in a pre-symptomatic child without an older affected sibling, (e.g.) incidentally or via newborn screening) and the totality of the data available to the investigator strongly suggest that the subject has an early onset variant of MLD likely to benefit from gene therapy, and the subject is <=6 years of age (i.e. has not celebrated 7th birthday), the subject may be considered eligible after discussion and approval by the GlaxoSmithKline medical monitor (GSK-MM).
- Parental/guardian signed and dated informed consent.
Exclusion criteria:
- Symptoms of MLD, defined as either of the following: a) delay in expected achievement of independent standing or independent walking, together with abnormal signs at neurological evaluation OR b) documented neurological signs and symptoms of MLD associated with cognitive, motor, or behavioral functional impairment or regression (substantiated by neurological examination and/or neuropsychological tests appropriate for age).
- Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
- Malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome. Subjects with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the GSK-MM.
- Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), or other serious hematological disorders.
- Subjects currently enrolled in other interventional trials.
- Has previously undergone allogeneic hematopoietic stem cell transplantation and has evidence of residual cells of donor origin.
- Previous gene therapy.
- Has symptomatic herpes zoster, not responsive to specific treatment. Subjects with a recent history of herpes zoster may be included in the study. In such cases, inclusion, additional monitoring and treatment of the condition must be discussed and approved by the GSK-MM.
- Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing i.e. QuantiFERON-TB Gold test and microbiological evidence. Subjects with latent tuberculosis, as documented by medical history and/or TB testing may be included in the study if receiving antibiotic prophylaxis (e.g. isoniazid). Inclusion, monitoring and treatment of TB in such subjects must be discussed and approved by the GSK-MM.
- Acute or chronic stable Hepatitis B as evidenced by positive Hepatitis B surface antigen (HBsAg) test result at screening or within 3 months prior to onset of conditioning and/or positive hepatitis B virus (HBV) DNA. Subjects with positive Hepatitis B core antibody due to prior resolved disease may be enrolled, only if a confirmatory negative Hepatitis B surface antigen and negative Hepatitis B DNA test are obtained. Inclusion, monitoring and treatment of hepatitis in such subjects must be discussed and approved by the GSK-MM.
- Presence of positive Hepatitis C RNA test result at screening; subjects who have previously tested positive for antibodies against hepatitis C can be treated, provided they demonstrate absence of ongoing infection using a nucleic acid test with a limit of quantification of <=15 international units/milliliter (IU/mL). Negative test results are required on at least 3 sequential occasions over a period of at least 4 weeks, after completion of treatment for hepatitis C, with the final test conducted no more than 3 days prior to cell harvest. Inclusion, monitoring and treatment of hepatitis in such subjects must be discussed and approved by the GSK-MM.
- End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgment of the investigator, would make the subject inappropriate for entry into this study. In addition to the potential infections the PI should consider testing for other transmissible infectious agents listed in the EU Cell and Tissue Directive as clinically appropriate and results discussed with the GSK-MM prior to cell harvest.
- Subjects with alanine transferase (ALT) >2x upper limit of normal (ULN) or total bilirubin >1.5xULN may be included only after discussed and agreed with the GSK-MM and considered in the context of the criterion for excluding subjects with other severe disease.
- Isolated elevation of total bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent of total.
Trial location(s)
Study documents
No study documents available.
Results overview
Study Results yet to be posted
Recruitment status
No longer a GSK study
Actual primary completion date
Not applicable
Actual study completion date
Not applicable
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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