Ignite Creation Date:
2024-05-06 @ 12:11 AM
Last Modification Date:
2024-10-26 @ 10:46 AM
Study NCT ID:
NCT01512888
Status:
SUSPENDED
Last Update Posted:
2024-04-17
First Post:
2012-01-13
Brief Title:
Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants
Sponsor:
St Jude Childrens Research Hospital
Organization:
St Jude Childrens Research Hospital
Study Overview
Official Title:
A Pilot Feasibility Study of Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants Using a Self-Inactivating Lentiviral Vector to Transduce Autologous CD34 Hematopoietic Cells
Status:
SUSPENDED
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
voluntary hold
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
LVXSCID-ND
Brief Summary:
SCID-X1 is a genetic disorder of blood cells caused by DNA changes in a gene that is required for the normal development of the human immune system The purpose of this study is to determine if a new method called lentiviral gene transfer can be used to treat SCID-X1 This method involves transferring a normal copy of the common gamma chain gene into the participants bone marrow stem cells The investigators want to determine if the procedure is safe whether it can be done according to the methods they have developed and whether the procedure will provide a normal immune system for the patient It is hoped that this type of gene transfer may offer a new way to treat children with SCID-X1 that do not have a brother or sister who can be used as a donor for stem cell transplantation
Detailed Description:
Bone marrow CD34 cells will be obtained in the operating room transduced with the lentiviral vector that contains a normal copy of the γc gene and reinfused without any myeloreductive conditioning Participants will be monitored for hematopoietic recovery from busulfan and for severe adverse events for 42 days post gene therapy The primary endpoint assessing the efficacy of this approach will be T-cell immune reconstitution 52 weeks 4 weeks after transplantation Continued and detailed evaluation of all aspects of immune reconstitution protocol-related toxicity and retroviral integration sites will also be performed This study will evaluate the first use of a SIN lentiviral vector for the treatment of SCID-X1 and may lead to a new form of therapy that could be applied to the majority of newly diagnosed patients
OBJECTIVES
Assess the safety feasibility and efficacy of lentiviral gene transfer in newly diagnosed SCID-X1 patients transplanted with autologous CD34 cells that have been transduced with a self-inactivating lentiviral vector CL20-i4-EF1α-hγc-OPT expressing a γc gene
Primary Objective 1 Evaluate the safety and feasibility of infusing at least 1 million transduced CD34 cells per kilogram of body weight in SCID-X1 infants
Primary Objective 2 Evaluate the efficacy of lentiviral gene transfer for inducing significant T-cell reconstitution 52 weeks 4 weeks after transplantation Significant reconstitution of T cells is defined as at least 2 of the following 3 criteria being present
The development of T-cell proliferative responses to phytohemagglutinin PHA that are 50 the value seen in normal controls
1000 autologous CD3 T-cellsμl in the peripheral blood
500 autologous CD4 T-cellsμl in the peripheral blood
200 autologous CD4 CD45RA T-cellsμl in the peripheral blood
OTHER PRE-SPECIFIED OBJECTIVES
Correlate busulfan and its metabolite pharmacokinetics with toxicity efficacy engraftment of vector-transduced cells and event-free survival and overall survival
Evaluate the efficacy of busulfan dose-targeting with busulfan administration every 24 hours for a total of 2 doses in order to achieve a cumulative busulfan area under the curve of 22 mghrL
Evaluate B-cell function during longterm follow-up of protocol patients Evaluation will include γc expression in circulating B-cells measurement of serum IgG IgA and IgM concentration measurement of antibody responses to vaccination evaluation of IgG production after cessation of intravenous gamma globulin therapy in patients with clinical indications to discontinue IVIG
Evaluate NK cell numbers in long term follow-up of protocol patients Evaluation will include flow cytometry evaluation of NK cell numbers
Determine the vector copy number and the location of vector-integration sites in sorted blood cells Sorted T-cells B-cells NK cells granulocytes and monocytes will be evaluated for vector copy number Vector copy number in sorted T-cells will be evaluated as a potential safety measure and will be reported to the FDA if the vector copy number is greater than 5 copies per T cell in any patient at any time Studies on sorted cells will also include deep sequencing with an automated sequencer to characterize insertion sites and expression array analysis of T-cell clones to assay for gene expression alterations within 100 kb of the insertion sites
Evaluate the overall long-term safety of lentiviral gene transfer This will include complete clinical evaluation of any AEs resulting from the gene transfer procedure If any oncogenic event is seen this evaluation will include complete molecular characterization of the tumor clone including insertion site analysis gene expression analysis and evaluation for the LMO2 Cdkn2a Notch1 Cyclin D2 gene alterations
OBJECTIVES
Assess the safety feasibility and efficacy of lentiviral gene transfer in newly diagnosed SCID-X1 patients transplanted with autologous CD34 cells that have been transduced with a self-inactivating lentiviral vector CL20-i4-EF1α-hγc-OPT expressing a γc gene
Primary Objective 1 Evaluate the safety and feasibility of infusing at least 1 million transduced CD34 cells per kilogram of body weight in SCID-X1 infants
Primary Objective 2 Evaluate the efficacy of lentiviral gene transfer for inducing significant T-cell reconstitution 52 weeks 4 weeks after transplantation Significant reconstitution of T cells is defined as at least 2 of the following 3 criteria being present
The development of T-cell proliferative responses to phytohemagglutinin PHA that are 50 the value seen in normal controls
1000 autologous CD3 T-cellsμl in the peripheral blood
500 autologous CD4 T-cellsμl in the peripheral blood
200 autologous CD4 CD45RA T-cellsμl in the peripheral blood
OTHER PRE-SPECIFIED OBJECTIVES
Correlate busulfan and its metabolite pharmacokinetics with toxicity efficacy engraftment of vector-transduced cells and event-free survival and overall survival
Evaluate the efficacy of busulfan dose-targeting with busulfan administration every 24 hours for a total of 2 doses in order to achieve a cumulative busulfan area under the curve of 22 mghrL
Evaluate B-cell function during longterm follow-up of protocol patients Evaluation will include γc expression in circulating B-cells measurement of serum IgG IgA and IgM concentration measurement of antibody responses to vaccination evaluation of IgG production after cessation of intravenous gamma globulin therapy in patients with clinical indications to discontinue IVIG
Evaluate NK cell numbers in long term follow-up of protocol patients Evaluation will include flow cytometry evaluation of NK cell numbers
Determine the vector copy number and the location of vector-integration sites in sorted blood cells Sorted T-cells B-cells NK cells granulocytes and monocytes will be evaluated for vector copy number Vector copy number in sorted T-cells will be evaluated as a potential safety measure and will be reported to the FDA if the vector copy number is greater than 5 copies per T cell in any patient at any time Studies on sorted cells will also include deep sequencing with an automated sequencer to characterize insertion sites and expression array analysis of T-cell clones to assay for gene expression alterations within 100 kb of the insertion sites
Evaluate the overall long-term safety of lentiviral gene transfer This will include complete clinical evaluation of any AEs resulting from the gene transfer procedure If any oncogenic event is seen this evaluation will include complete molecular characterization of the tumor clone including insertion site analysis gene expression analysis and evaluation for the LMO2 Cdkn2a Notch1 Cyclin D2 gene alterations
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| P01HL053749 | NIH | None | httpsreporternihgovquickSearchP01HL053749 |