- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01129544
Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
Multi-site Phase I/II Trial Evaluating the Treatment of SCID-X1 Patients With Retrovirus-mediated Gene Transfer
Researchers are working on ways to treat SCID patients who don't have a matched brother or sister. One of the goals is to avoid the problems that happen with stem cell transplant from parents and unrelated people, such as repeat transplants, incomplete cure of the immune system, exposure to chemotherapy, and graft versus host disease.
The idea behind gene transfer is to replace the broken gene by putting a piece of genetic material (DNA) that has the normal gene into the child's cells. Gene transfer can only be done if we know which gene is missing or broken in the patient. For SCID-X1, gene transfer has been done in the laboratory and in two previous clinical trials by inserting the normal gene into stem cells from bone marrow. The bone marrow is the "factory" inside the bones that creates blood and immune cells. So fixing the gene in the bone marrow stem cells should fix the immune problem, without giving chemotherapy and without risk of graft versus host disease, because the child's own cells are used, rather than another person's. Out of the 20 subjects enrolled in the two previous trials, 18 are alive with better immune systems after gene transfer. Two of the surviving subjects received gene corrected cells over 10 years ago.
Gene transfer is still research for two reasons. One is that not enough children have been studied to tell if the procedure is consistently successful. Of the 20 children enrolled in the previous two trials, one child did not have correction of the immune system, and died of complications after undergoing stem cell transplant. The second important reason why gene transfer is research is that we are still learning about the side effects of gene transfer and how to do gene transfer safely. In the last two trials, 5 children have experienced a serious side effect. These children developed leukemia related to the gene transfer itself. Leukemia is a cancer of the white blood cells, a condition where a few white blood cells grow out of control. Of these children, 4 of the 5 have received chemotherapy (medication to treat cancer) and are currently in remission (no leukemia can be found by sensitive testing), whereas one died of gene transfer-related leukemia.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
California
-
Los Angeles, California, United States, 90095
- Mattel Children's Hospital - UCLA
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02116
- Children's Hospital Boston
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Ohio
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Cincinnati, Ohio, United States, 45229
- Cincinnati Children's Medical Center
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
Diagnosis of SCID-X1 based on immunophenotype (<200 CD3+ autologous T cells, and confirmed by DNA sequencing)
AND
- Lack an HLA identical (A, B, C, DR, DQ) related donor
AND either one of the following:
1. Patients in good clinical condition who do not have a readily available HLA identical (A,B,C,DR,DQ) unrelated donor (readily available defined as: a donor confirmed within 6 weeks of searching, with ability to transplant within 3 months of diagnosis).
2. Patients with an active, therapy-resistant infection or other medical conditions that significantly increase the risk of allogeneic transplant. Examples of "therapy-resistant infections that significantly increase the risk of allogeneic transplant" include but are not limited to:
- interstitial pneumonia due to adenovirus or parainfluenzae virus.
- protracted diarrhea requiring total parenteral nutrition.
- disseminated BCG infection.
- virus-induced lymphoproliferative disease.
- any active opportunistic infection (eg, due to Pneumocystis jiroveci, cytomegalovirus,cryptosporidium) that does not improve on medical management.
- active and progressive pulmonary disease requiring mechanic ventilation. Inclusion of patients with disease-related organ dysfunction is justified by the known poor outcome with standard treatment and the potential life-saving nature of the treatment proposed. Patients who are on high-dose steroids or other immunosuppressive agents will also be considered eligible, because use of these drugs is common in patients with SCID and maternal T cell engraftment or who present with severe interstitial lung disease. Use of immunosuppressive drugs does not affect efficacy of hematopoietic cell transplantation, and therefore should not affect efficacy of gene transfer.
Exclusion Criteria:
- No available molecular diagnosis confirming SCID-X1.
- Patients who have an available HLA-identical related donor.
- Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
- Patients with evidence of infection with HIV-1
- Previous gene transfer
- Major (life-threatening) congenital anomalies. Examples of "major (life-threatening) congenital anomalies" include, but are not limited to: unrepaired cyanotic heart disease, hypoplastic lungs, anencephaly or other major CNS malformations, other severe non-repairable malformations of the gastrointestinal or genitourinary tracts that significantly impair organ function.
- Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate collection and/or infusion of transduced cells or indicate patient's inability to follow the protocol. These may include for example clinical ineligibility to receive anesthesia, severe deterioration of clinical condition of the patient after collection of bone marrow but before infusion of transduced cells, or documented refusal or inability of the family to return for scheduled visits. There may be other unforeseen rare circumstances that would result in exclusion of the patient, such as sudden loss of legal guardianship.
Although the presentation of the disease may be variable in type, the severity of the immunodeficiency is uniform. The gene transfer protocol will be instituted in the place of haploidentical transplant for those patients who do not have a matched family donor or in whom an unrelated donor transplant is not indicated for the reasons specified above. Apart from the gene transfer protocol, the patients will not undergo additional procedures that would not form part of an equivalent haploidentical transplantation regimen, and will not receive conditioning chemotherapy.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Gene Transfer
open label single arm study
|
Three procedures: 1) Bone marrow harvest from the patient's posterior iliac crests.
2.) Chemotherapy conditioning with Busulfan 3)One time infusion of patient's transduced bone marrow cells.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
CD3 cell count post transfusion
Time Frame: 6 Months Post Gene Transfer
|
Immunological reconstitution defined as absolute CD3 cells of >300/μl and PHA stimulation index >15 at 6 months post infusion
|
6 Months Post Gene Transfer
|
Incidence of life-threatening adverse reactions related to the gene therapy procedure.
Time Frame: Up to 15 years post gene transfer
|
Incidence of life-threatening adverse reactions related to the gene therapy procedure.
|
Up to 15 years post gene transfer
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Molecular characterization of gene transfer.
Time Frame: Up to 15 years post gene transfer
|
Up to 15 years post gene transfer
|
Ability to mount antibody responses to vaccination.
Time Frame: Within 18 Months post standard vaccination to tentanus
|
Within 18 Months post standard vaccination to tentanus
|
Normalization of nutritional status, growth, and development
Time Frame: Up to 15 years post gene transfer
|
Up to 15 years post gene transfer
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Jennifer Whangbo, MD, Boston Children's Hospital
Publications and helpful links
General Publications
- Clarke EL, Connell AJ, Six E, Kadry NA, Abbas AA, Hwang Y, Everett JK, Hofstaedter CE, Marsh R, Armant M, Kelsen J, Notarangelo LD, Collman RG, Hacein-Bey-Abina S, Kohn DB, Cavazzana M, Fischer A, Williams DA, Pai SY, Bushman FD. T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency. Genome Med. 2018 Sep 28;10(1):70. doi: 10.1186/s13073-018-0580-z.
- Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernandez KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med. 2014 Oct 9;371(15):1407-17. doi: 10.1056/NEJMoa1404588.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- IND14067
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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