ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin Gene
The patient has inherited ß-thalassemia major through the genes. These genes have mistakes in them, so the body cannot make normal red blood cells. Stem cells are made in the bone marrow. They are the earliest form of blood cells.
This study is being done to see if the investigators can make the stem cells produce normal red blood cells and hemoglobin. The investigators do this by collecting the stem cells. The genes with mistakes are removed from the cells. These cells are then treated so they have the corrected gene for making normal hemoglobin. These treated cells are given back to the patient through an injection (shot) in the vein. This is also known as gene transfer. In order for the body to accept these cells, the patient will need to receive a low dose of a drug called busulfan. It is a drug that will prepare the body to receive the new stem cells.
This study will let the investigators know:
- If it is safe to give the patient the treated stem cells
- If the treated stem cells will go into the bone marrow without causing side effects.
Gene transfer has been used for the past five years. It has been successful in treating many blood disorders. At least 20 patients have received the type of treatment that the patient will get on this study. This treatment for B-thalassemia major was developed here at Memorial Sloan Kettering (MSK). It was studied for a long time in the lab before being given to patients.
|Confirmed Diagnosis of ß-thalassemia Major||Genetic: Autologous CD34+ cells transduced with TNS9.3.55||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Phase I Clinical Trial for the Treatment of ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin Gene|
- safety [ Time Frame: 2 years ]
of transplanted autologous CD34+ hematopoietic cells that are transduced ex vivo with TNS9.3.55 and transplanted in subjects with ß-thalassemia major conditioned with a reduced-intensity non-myeloablative preparative regimen.
- The occurrence of insertional oncogenesis, which will be investigated by monitoring peripheral blood cell counts and leukocyte clonality using FACS analysis, qPCR for vector. copy number, LAM-PCR and/or 454 sequencing;
- The generation of a replication-competent lentivirus (RCL).
- The safety of a low dose non-myeloablative conditioning regimen
- tolerability [ Time Frame: 2 years ]of transplanted autologous CD34+ hematopoietic cells that are transduced ex vivo with TNS9.3.55 & transplanted in subjects with ß-thalassemia major conditioned with a reduced-intensity non-myeloablative preparative regimen. monitoring the following: 1. The occurrence of insertional oncogenesis, which will be investigated by monitoring peripheral blood cell counts & leukocyte clonality using FACS analysis, qPCR for vector. copy number, LAM-PCR and/or 454 sequencing; 2.The generation of a replication-competent lentivirus (RCL). 3.The safety of a low dose non-myeloablative conditioning regimen
- the level of engraftment [ Time Frame: 2 years ]
of the genetically modified autologous CD34+ cells and expression of the transduced ß-globin gene as measured by: Blood for measurement of vector copy number and transgene expression in blood cells at months 1, 2 and 3.
- Bone Marrow Samples for evaluation of CFU, BFU-E gene+ colonies and Q-PCR will be tested at month 1.
- The frequency of post transplant palliative transfusions [ Time Frame: 2 years ]The number of red blood cell transfusions after engraftment will be quantitatively evaluated for efficacy purposes.
|Study Start Date:||July 2012|
|Estimated Study Completion Date:||July 2018|
|Estimated Primary Completion Date:||July 2018 (Final data collection date for primary outcome measure)|
Experimental: Autologous CD34+ cells transduced with TNS9.3.55
An open label study using a non-myeloablative conditioning regimen of busulfan and 1 or several infusions of autologous hematopoietic stem cells transduced with a lentiviral vector encoding the human ß-globin gene.
Genetic: Autologous CD34+ cells transduced with TNS9.3.55
Patients will receive Filgrastim followed by apheresis of peripheral blood stem cells. CD34+ cells will be purified and transduced ex vivo. Transduced cells will be frozen in several aliquots whenever possible while vector copy number determination and biosafety testing are performed. Patients will be treated in the outpatient and/or inpatient units, and receive intravenous busulfan (8mg/kg) as non-myeloablative conditioning. Patients will be administered 2-12 x 10^6 transduced CD34+ cells per kg in 1 or several infusions. A back-up of 2 x 10^6 untransduced CD34+ cells per kg will be preserved for every patient.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01639690
|United States, New York|
|Memorial Sloan Kettering Cancer Center|
|New York, New York, United States, 10065|
|Principal Investigator:||Farid Boulad, MD||Memorial Sloan Kettering Cancer Center|