This study is currently recruiting participants. Verified July 2012 by Memorial Sloan-Kettering Cancer Center

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1 Home Search Study Topics Glossary Search Full Text View Tabular View No Study Results Posted Related Studies Treatment of ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With Thalagen, a Lentiviral Vector Encoding the Normal Human ß- Globin Gene This study is currently recruiting participants. Verified July 2012 by First Received on July 11, Last Updated on July 12, 2012 History of Changes Sponsor: Collaborator: Information provided by (Responsible Party): ClinicalTrials.gov Identifier: Errant Gene Therapeutics NCT Purpose The patient inherited B-thalassemia major through their 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 investigators can make the stem cells produce normal red blood cells and hemoglobin. The investigators do this by collecting a patients 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, it 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 investigators know: If it is safe to give 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 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. Condition Intervention Phase Confirmed Diagnosis of ß-thalassemia Major Genetic: Autologous CD34+ cells transduced with TNS (Thalagen ) Phase 1 Study Type: Study Design: Official Title: Interventional Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment A Phase I Clinical Trial for the Treatment of ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With Thalagen, a Lentiviral Vector Encoding the Normal Human ß-Globin Gene Resource links provided by NLM: Genetics Home Reference related topics: Help Me Understand Genetics MedlinePlus related topics: Thalassemia

2 Drug Information available for: Busulfan U.S. FDA Resources Further study details as provided by : Primary Outcome Measures: safety [ Time Frame: 2 years ] [ Designated as safety issue: Yes ] of Thalagen -CD34+, in this patient cohort. This will be evaluated through monitoring the following: 1. 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; 2. The generation of a replication-competent lentivirus (RCL). 3. The safety of a low dose non-myeloablative conditioning regimen. tolerability [ Time Frame: 2 years ] [ Designated as safety issue: No ] of Thalagen -CD34+, in this patient cohort. This will be evaluated through monitoring the following: 1. 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; 2. The generation of a replication-competent lentivirus (RCL). 3. The safety of a low dose non-myeloablative conditioning regimen. Secondary Outcome Measures: the level of engraftment [ Time Frame: 2 years ] [ Designated as safety issue: No ] of transduced CD34+ cells and the biological activity of the globin vector, as measured by: 1. The presence and expression of the transduced ß-globin transgene in peripheral blood cells; and the presence and expression of the transgene in hematopoietic progenitor cells in bone marrow; 2. The frequency of palliative transfusions subsequent to transplantation. Estimated Enrollment: 10 Study Start Date: July 2012 Estimated Study Completion Date: July 2014 Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure) Arms Experimental: Autologous CD34+ cells transduced with TNS (Thalagen ), An open label study using a non-myeloablative conditioning regimen of busulfan and 1 or 2 infusions of autologous hematopoietic stem cells transduced with a lentiviral vector encoding the human ß-globin gene. Assigned Interventions Genetic: Autologous CD34+ cells transduced with TNS (Thalagen ) 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 2 aliquots whenever possible while vector copy number determination and biosafety testing are performed. Patients will be admitted, and receive intravenous busulfan (8mg/kg) as non-myeloablative conditioning. Patients will be administered 2-8 x 106 transduced CD34+ cells per kg in 1-2 infusions. A back-up of 2 x 106 untransduced CD34+ cells per kg or more will be preserved for every patient. Eligibility Ages Eligible for Study: Genders Eligible for Study: 15 Years and older Both

3 Accepts Healthy Volunteers: No Criteria Inclusion Criteria: Subjects must be 15 years or older Subjects may be of either gender or of any ethnic background Subjects must have a confirmed diagnosis of ß-thalassemia major and have been enrolled in a hypertransfusion program with a confirmed annual transfusion of 100 ml/kg/yr but < 200 ml/kg/yr, AND 8 transfusions of blood per year over a minimum of two years. Patients must NOT have an HLA-matched sibling Patients must be off hydroxyurea (HU) or erythropoietin (EPO) treatment for at least three months prior to entry onto the study Subjects must have a performance score of Karnofsky >70% at the time of entry into the study. Subjects must have had a liver biopsy performed within the one year period prior to entry onto the study. This must include pathological evaluation for iron content and fibrosis, and liver tissue specimen evaluated at the Mayo Clinic Mayo Medical Laboratory (Rochester, MN) ( for iron quantitation**. Subjects must have liver iron value of < 15 mg/g/dry weight and no evidence of cirrhosis**. Subjects with an evaluation of cardiac function indicating: Normal function on MUGA scan (Multiple Gated Acquisition scan). Patients must have a left ventricular ejection fraction (LVEF) of > 60% T2*MRI cardiac evaluation with T2* >20 milliseconds Subjects with asymptomatic pulmonary function based on Lung Diffusion Testing DLCO Test DLCO > 50% of predicted (corrected for hemoglobin) Subjects with a determination of renal function based on: serum creatinine <1.5 mg/dl or if serum creatinine is outside the normal range, then CrCl > 60-ml/min/1.73 m2 Subjects must have adequate hepatic function based on: < 3 x ULN ALT and < 2.0 total serum bilirubin (unless secondary to hemolysis) Patients must be available for follow-up evaluations at 30, 60, 180 days post BMT and yearly thereafter indefinitely. Exclusion Criteria: The possibility of unrelated donor stem cell transplantation will be discussed with patients, and a "preliminary" search for an unrelated donor may be done at the request of the patient. However, the finding of a potential HLA-matched unrelated donor will not exclude the patient from participating into this trial). As the inclusion criteria are more specific than the Lucarelli/Pesaro thalassemia pre-transplant classification (Class 1,2 or 3 according to presence or absence of fibrosis, adequate chelation and/or hepatomegaly), the criteria stated above will be used in lieu of the Lucarelli/Pesaro classification. Active infections including Hepatitis B and hepatitis C***, Active infections including HTLV 1 and 2, and HIV 1 and 2 Patients with treated HLTC or HIV Diabetes Mellitus Bone Marrow myelodysplasia and/or chromosomal abnormalities Female patient pregnant or breast feeding Patients with uncontrolled seizure disorders Patients with severe pulmonary hypertension Tricuspid Jet velocity > 2.5 m/sec Family history of familial cancer syndromes (leukemia, breast, ovarian, colorectal, etc.) *** Definition of active hepatitis C include: Positive HCV RNA Viral load by quantitative PCR testing Or if Negative HCV RNA viral load BUT on antiviral treatment Liver biopsy with pathologic evidence of Necrosis and inflammation around the portal areas - piecemeal necrosis or interface hepatitis or necrosis of hepatocytes and focal inflammation in the liver parenchyma. Inflammatory cells in the portal areas ("portal inflammation"). Fibrosis, with early stages being confined to the portal tracts, intermediate stages being expansion of the portal tracts and bridging between portal areas or to the central area, and late stages being frank cirrhosis

4 characterized by architectural disruption of the liver with fibrosis and regeneration. Contacts and Locations Please refer to this study by its ClinicalTrials.gov identifier: NCT Contacts Contact: Farid Boulad, MD Contact: Susan Prockop, MD Locations United States, New York Recruiting New York, New York, United States, Contact: Farid Boulad, MD Contact: Susan Prockop, MD Principal Investigator: Farid Boulad, MD Sponsors and Collaborators Errant Gene Therapeutics Investigators Principal Investigator: Farid Boulad, MD More Information Additional Information: No publications provided Responsible Party: ClinicalTrials.gov Identifier: NCT History of Changes Other Study ID Numbers: Study First Received: July 11, 2012 Last Updated: July 12, 2012 Health Authority: United States: Food and Drug Administration Keywords provided by : BUSULFAN G-CSF Thalagen beta-globin gene transduced HPCs Additional relevant MeSH terms: Beta-Thalassemia Thalassemia Anemia, Hemolytic, Congenital Anemia, Hemolytic CliniMACS-CD34 Reagent System Blood transfusion Anemia Hematologic Diseases Hemoglobinopathies Genetic Diseases, Inborn ClinicalTrials.gov processed this record on July 12, 2012 Contact Help Desk Lister Hill National Center for Biomedical Communications, U.S. National Library of Medicine, U.S. National Institutes of Health, U.S. Department of Health & Human Services, USA.gov, Copyright, Privacy, Accessibility, Freedom of Information Act

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