Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants (LVXSCID-ND)
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|ClinicalTrials.gov Identifier: NCT01512888|
Recruitment Status : Suspended (voluntary hold)
First Posted : January 19, 2012
Last Update Posted : April 19, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Severe Combined Immunodeficiency Disease, X-linked||Genetic: CL20-i4-EF1α-hγc-OPT Drug: Busulfan Device: CliniMacs||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||28 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||August 17, 2016|
|Estimated Primary Completion Date :||August 2025|
|Estimated Study Completion Date :||August 2034|
Participants will undergo a bone marrow harvest in the operating room to obtain bone marrow cells. Cells will be isolated and purified utilizing the CliniMacs device. These cells will undergo vector transduction with the lentiviral vector that contains a normal copy of the γc gene gene (CL20-i4-EF1α-hγc-OPT) and then the transduced cells will 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-i4-EF1α-hγc-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.
Given intravenously (IV).
Isolation and purification of CD34+ stem cells will be done after the unmodified frozen backup is obtained and in accordance with our FDA IND and in accordance with the CliniMacs manual of operations.
- Number of patients with adequate cell collection and processing [ Time Frame: Day 0 ]The number of patients who underwent no more than two bone marrow harvests and cryopreservation of at least 1.0 million cells/kg following vector transduction.
- Number of patients with adequate neutrophil count recovery after busulfan conditioning [ Time Frame: Day 42 post gene transfer ]Adequate recovery is defined as absolute neutrophil count (ANC) >500 cells/μl by day +42 unless the patient is neutropenic prior to busulfan administration.
- Number of patients without Grade 4 adverse event (AE) [ Time Frame: 42 days post gene transfer ]The number of patients experiencing no directly related grade 4 or greater adverse event.
- Number of patients with successful reconstitution [ Time Frame: 42 days post gene transfer ]Reconstitution with transduced cells defined as detection of vector-marked peripheral blood cells by real time PCR at or above 0.02% VCN in total WBC.
- Number of patients with treatment failure [ Time Frame: 42 days post gene transfer ]Treatment failure will be defined as lack of adequate cell collection and processing, lack of neutrophil count recovery by day +42, occurrence of grade 4 or greater toxicities by day +42, and/or lack of detection of >0.02% transduced cells in peripheral blood by day +42 post gene transfer.
- Pharmacokinetic (PK) variables of busulfan [ Time Frame: Days -2 and -1 prior to therapy ]Blood collections for pharmacokinetic sampling will be performed with dose 1 and used to determine dose modifications for dose 2, if needed. The specific times for blood collects will be institution specific. Summary statistics will be reported.
- Number of patients who achieve the desired therapeutic busulfan AUC [ Time Frame: Day 0 ]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 AUC of 22 mg*hr/L will be evaluated. The number of patients who achieve the desired therapeutic busulfan AUC will be reported
- B-cell function evaluated by Immune response [ Time Frame: 52 weeks post gene transfer ]Evaluation may 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. Summary statistics will be reported.
- Number of NK cells [ Time Frame: 52 weeks post gene transfer ]Evaluation will include flow cytometry evaluation of NK cell numbers. Summary statistics will be reported.
- Vector copy number by location of vector-integration sites in sorted blood cells [ Time Frame: up to 10 years post gene transfer ]Sorted T-cells, B-cells, NK cells, granulocytes and monocytes will be evaluated for vector copy number. 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. Summary statistics will be reported.
- Event-free survival (EFS) [ Time Frame: from baseline up to 10 years post gene transfer ]Event is defined as death, requiring boost post infusion, or an oncogenic event . EFS is defined as time from busulfan infusion to event defined here with all patients surviving at the time of analysis censored.
- Overall survival (OS) [ Time Frame: up to 10 years post gene transfer ]OS is defined as time from busulfan infusion to death with all patients surviving at the time of analysis censored.
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|Ages Eligible for Study:||up to 24 Months (Child)|
|Sexes Eligible for Study:||Male|
|Gender Based Eligibility:||Yes|
|Accepts Healthy Volunteers:||No|
* Treatment Eligibility Criteria:
- Age <2 years at the time of enrollment.
- No prior therapy with allogeneic stem cell transplantation.
- A clinical diagnosis of SCID-X1 documented in the medical record.
- A proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA.
- Age > 2 months to < 1 year of age at the time of busulfan administration.
- Less than 300 CD3+ T-cells by flow cytometry or higher if evidence of maternal engraftment as supported by peripheral blood FISH analysis for XY and XX.
- Lymphocyte proliferation to phytohemagglutinin (PHA) <10% of the lower limit of normal for the laboratory.
Treatment Exclusion Criteria:
- Availability of a HLA matched sibling for allogeneic transplantation
- Prior therapy with allogeneic stem cell transplantation
- Positive for HIV infection by genome PCR
- Presence of a medical condition indicating that survival will be less than 16 weeks such as the requirement for mechanical ventilation, severe failure of a major organ system, or evidence of a serious, progressive infection that is refractory to medical therapy.
- The presence of any medical contraindications to general anesthesia and bone marrow harvest by aspiration
- A social situation indicating that the family may not be able to comply with protocol procedures and recommended medical care.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01512888
|United States, California|
|University of California-San Francisco|
|San Francisco, California, United States, 94158|
|United States, Tennessee|
|St. Jude Children's Research Hospital|
|Memphis, Tennessee, United States, 38105|
|United States, Washington|
|Seattle Children's Research Institute|
|Seattle, Washington, United States, 98101|
|Principal Investigator:||Stephen Gottschalk, MD||St. Jude Children's Research Hospital|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||St. Jude Children's Research Hospital|
|Other Study ID Numbers:||
P01HL053749 ( U.S. NIH Grant/Contract )
|First Posted:||January 19, 2012 Key Record Dates|
|Last Update Posted:||April 19, 2023|
|Last Verified:||April 2023|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||Yes|
X-Linked Combined Immunodeficiency Diseases
Severe Combined Immunodeficiency
Immunologic Deficiency Syndromes
Immune System Diseases
Primary Immunodeficiency Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Genetic Diseases, X-Linked
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating