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 (PK) variables of busulfan [ Time Frame: Days -2 and -1 prior to therapy, and at hours 3, 4, 6, and 8 after the start of infusion on both days ] [ 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 comply with institutional requirements regarding maximum blood draw volume and sample collection times. Institutions other than St. Jude may have slightly different times for drawing blood for PK analysis.
- Number of participants with early T-cell reconstitution [ Time Frame: 52 weeks post reinfusion of lentiviral vector ] [ Designated as safety issue: No ]
- Protocol-related toxicity [ Time Frame: from baseline up to 10 years ] [ Designated as safety issue: Yes ]
- Event-free survival (EFS) [ Time Frame: from baseline up to 10 years ] [ Designated as safety issue: Yes ]
- Overall survival (OS) [ Time Frame: up to 10 years ] [ Designated as safety issue: No ]
- Number of patients who achieve a cumulative busulfan area under the curve (AUC) of 11 mg*hr/L [ Time Frame: 16 weeks post gene therapy ] [ 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
- 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 mg*hr/L.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01512888
|Contact: Brian Sorrentino, MDemail@example.com|
|Contact: Ewelina Mamcarz, MDfirstname.lastname@example.org|
|United States, California|
|University of California-San Francisco||Not yet recruiting|
|San Francisco, California, United States, 94158|
|Contact: Mort Cowan, MD 415-476-2656 email@example.com|
|Principal Investigator: Mort Cowan, MD|
|Sub-Investigator: Jennifer Puck, MD|
|United States, Tennessee|
|St. Jude Children's Research Hospital||Recruiting|
|Memphis, Tennessee, United States, 38105|
|Contact: Brian Sorrentino, MD 901-595-2727 firstname.lastname@example.org|
|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: Andrew M. Scharenberg, MD 206-987-7450 email@example.com|
|Principal Investigator: Andrew M. Scharenberg, MD|
|Sub-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|
|Sub-Investigator: Lauri M. Burroughs, MD|
|Principal Investigator:||Brian Sorrentino, MD||St. Jude Children's Research Hospital|