Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants (LVXSCID-ND)
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 participant's 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.
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 3 million CD34+ cells per kilogram of body weight.
- Number of patients with early T-Cell reconstitution without Grade 3 AE (Phase I) [ Time Frame: 16 Weeks from enrollment ] [ 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.
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).
Other Name: Busulfex®
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 3 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: Brandon Triplett, MD|
|United States, Washington|
|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|
|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|
|Principal Investigator:||Brian Sorrentino, MD||St. Jude Children's Research Hospital|