Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants (LVXSCID-ND)
Severe Combined Immunodeficiency Disease, X-linked
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- Number of patients successfully infused with the CD34+ Cells. (Phase I) [ Time Frame: 16 Weeks from enrollment ] [ Designated as safety issue: Yes ]The number of patients who were successfully infused with at least 1 million CD34+ cells per kilogram of body weight.
- Number of patients with early T-Cell reconstitution without Grade 3 AE (Phase I) [ Time Frame: up to 17 Weeks post gene transfer ] [ Designated as safety issue: Yes ]The number of patients meeting the following criteria: No directly related grade 3 or greater adverse events and the presence of at least one marker of early T-cell reconstitution.
- The number of patients with effective Lentiviral Gene Transfer (Phase II) [ Time Frame: 52 Weeks from enrollment ] [ Designated as safety issue: Yes ]Number of patients with effective lentiviral gene transfer for inducing significant T-cell reconstitution.
- Pharmacokinetic variables of busulfan [ Time Frame: Days -3 and -2 prior to therapy, and at hours 3, 3.25, 6, 8, 11, 18, and 24 after start of infusion. ] [ Designated as safety issue: No ]This outcome will not be analyzed for participants <3kg, For participants ≥3 to <6 kg, evaluation will be limited to pre-therapy and at hours 3, 3.25, 8, and 24 to comply with institutional requirements regarding maximum blood draw volume and sample collection times.
- Pre-busulfan metabolomics of busulfan [ Time Frame: Day -4 prior to therapy ] [ Designated as safety issue: No ]
- Change in pre-graft metabolomics of busulfan [ Time Frame: Day 0 immediately prior to therapy and approximately 72 hours after the first dose of busulfan ] [ Designated as safety issue: No ]
|Study Start Date:||February 2012|
|Estimated Study Completion Date:||February 2029|
|Estimated Primary Completion Date:||February 2019 (Final data collection date for primary outcome measure)|
Participants will undergo a bone marrow harvest in the operating room to obtain bone marrow cells. These cells will undergo vector transduction with the lentiviral vector that contains a normal copy of the γc gene gene (CL20-4i-EF/a-hyc-OPT) and then the transduced cells be reinfused back into the patient. Participants will receive a conditioning regimen of busulfan 3 days prior and 2 days prior to infusion of vector-corrected cells.intervention: CL20-4i-EF/a-hyc-OPT
Participants will undergo infusion with autologous CD34+ bone marrow cells transduced with a lentiviral vector that contains a normal copy of the human γc gene.
Other Names:Drug: Busulfan
Given intravenously (IV).
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. Patients who do not show evidence for early T-cell reconstitution by 16 (+ 1) weeks after cell infusion will be considered an early failure and offered an allogeneic transplant. For all other patients, the primary endpoint assessing the efficacy of this approach will be T-cell immune reconstitution 52 weeks (+ 2) 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.
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 obtaining and infusing at least 1 million CD34+ cells per kilogram of body weight in SCID-X1 infants.
Primary Objective 2: Assess the safety of the study procedure and assess for early evidence of significant T-cell reconstitution at 16 (± 1) weeks as defined by no grade 3 or greater adverse events that are directly related to the gene transfer procedure AND the presence of at least one of the following: 1) greater than 500 T-cell receptor excision circles (TRECs) per µg of DNA OR 2) the development of T-cell proliferative responses to phytohemagglutinin (PHA) that are ≥ 25 % of the value seen in normal controls OR 3) greater than 150 cells/ul CD3+ T-cells in the peripheral blood.
Primary Objective 3: Evaluate the efficacy of lentiviral gene transfer for inducing significant T-cell reconstitution 52 weeks (± 2 weeks) after transplantation. Significant reconstitution of T cells is defined as at least 2 of the following 3 criteria being present:
- Greater than 1000 copies of T-cell receptor excision circles (TRECs) per µg of DNA from peripheral blood mononuclear cells
- the development of T-cell proliferative responses to phytohemagglutinin (PHA) that are ≥ 50% the value seen in normal controls
- ≥ 300 cells/ul CD3+ T-cells in the peripheral blood
Please refer to this study by its ClinicalTrials.gov identifier: NCT01512888
|Contact: Brian Sorrentino, MDfirstname.lastname@example.org|
|United States, Tennessee|
|St. Jude Children's Research Hospital||Recruiting|
|Memphis, Tennessee, United States, 38105|
|Contact: Brian Sorrentino, MD 866-278-5833 email@example.com|
|Principal Investigator: Brian Sorrentino, MD|
|Sub-Investigator: Ewelina Mamcarz, MD|
|United States, Washington|
|Seattle Children's Research Institute||Not yet recruiting|
|Seattle, Washington, United States, 98101|
|Contact: David J. Rawlings, MD 206-987-7450|
|Principal Investigator: Andrew M. Scharenberg, MD|
|Principal Investigator: David J. Rawlings, MD|
|Fred Hutchinson Cancer Research Center||Not yet recruiting|
|Seattle, Washington, United States, 98109|
|Contact: Lauri M. Burroughs, MD 206-667-2396 firstname.lastname@example.org|
|Principal Investigator: Lauri M. Burroughs, MD|
|Principal Investigator:||Brian Sorrentino, MD||St. Jude Children's Research Hospital|