Gene Therapy for Transfusion Dependent Beta-thalassemia
NCT ID: NCT02453477
Last Updated: 2019-06-28
Study Results
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Basic Information
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UNKNOWN
PHASE1/PHASE2
10 participants
INTERVENTIONAL
2015-05-31
2019-08-31
Brief Summary
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Detailed Description
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This study will enroll 10 patients allocated in 3 groups, according to age and conditioning regimen:
1. 3 adults (≥18 years) conditioned with treosulfan and thiotepa
2. 3 elderly children (8-17 years) conditioned with treosulfan and thiotepa
3. 4 younger children (3-7 years) conditioned with treosulfan and thiotepa Enrolment will start in adult patients. Pediatric patients will be included once evidence of preliminary safety and biological efficacy is shown in at least 2 adults.
Patients are included regardless of the beta globin gene mutation, provided an adequate cardiac, renal, hepatic and pulmonary function is demonstrated. Patients with severe iron overload are excluded as well as patients with active viral infections. Pediatric patients can be enrolled only in absence of a human leukocyte antigen (HLA)-identical sibling or a suitable 10/10 matched unrelated donor.
The treated patients will be followed for 2 years. After completion of the 2 years follow up, patients will be enrolled in a long term follow up study and followed up for at least other additional 6 years.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Adults
≥18 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium.
Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells.
The product will be injected intraosseously.
Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the human beta-globin gene resuspended in their final formulation medium. The target dose in the transduced product is 5x10\^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10\^6/Kg and a maximum dose of 20 x 10\^6/Kg, depending on the yield of cells. The product will be injected intraosseously.
Elderly children
8-17 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium.
Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells.
The product will be injected intraosseously.
Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the human beta-globin gene resuspended in their final formulation medium. The target dose in the transduced product is 5x10\^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10\^6/Kg and a maximum dose of 20 x 10\^6/Kg, depending on the yield of cells. The product will be injected intraosseously.
Younger children
3-7 years (4 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium.
Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells.
The product will be injected intraosseously.
Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the human beta-globin gene resuspended in their final formulation medium. The target dose in the transduced product is 5x10\^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10\^6/Kg and a maximum dose of 20 x 10\^6/Kg, depending on the yield of cells. The product will be injected intraosseously.
Interventions
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Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the human beta-globin gene resuspended in their final formulation medium. The target dose in the transduced product is 5x10\^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10\^6/Kg and a maximum dose of 20 x 10\^6/Kg, depending on the yield of cells. The product will be injected intraosseously.
Eligibility Criteria
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Inclusion Criteria
* Transfusion-dependent beta-thalassemia (any genotype). Transfusion dependence is defined as receiving ≥ 8 transfusions of blood per year over a minimum of 2 years.
* Karnofsky Index or Lansky \> 80%
* Age ≥ 3 years and \< 65 years
* Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
* Left ventricular ejection fraction (LVEF) greater than 45% by echo and normal ECG or presence of abnormalities not significant for cardiac disease. Absence of severe pulmonary hypertension
* Diffusing capacity of the lung for carbon monoxide (DLCO) \> 50% and forced expiratory volume in 1 sec (FEV1) and forced expiratory vital capacity (FVC) \> 60% predicted (if non cooperative: pulse oximetry \> 95 % in room air)
* Serum creatinine \< 1.5 upper limit of normal
* Absent-mild-moderate liver iron overload on T2\*MRI (less than 12 months before enrolment)
* Absent-mild-moderate cardiac iron overload T2\*MRI (less than 12 months before enrolment)
* Absence of severe liver fibrosis or cirrhosis on fibroscan or liver biopsy (less than 12 months before enrolment)
* Low risk thrombophilic screen and negative history of significant previous thrombotic events
* For all patients in reproductive age, agreement to use highly effective and adequate method of contraception while receiving treatment phase and for at least 12 months following drugs administration (including both females of child bearing potential and males with partners of child bearing potential)
* Good adherence to transfusion and chelation programme as indirect evidence of good adherence to treatment and follow-up evaluations for current trial
* Availability of an adequate and well documented transfusion history (at least previous 6 months) or availability to follow a regular transfusion regimen according to guidelines and provide a detailed transfusion record of the 6 months prior to intervention phase
Exclusion Criteria
* Severe, active viral, bacterial, or fungal infection at eligibility evaluation
* Malignant neoplasia (except local skin cancer or cervical intraepithelial neoplasia) or exceptional family history of familial cancer syndromes
* Myelodysplasia, cytogenetic alterations associated with neoplasia, or other serious haematological disorder than thalassemia
* History of uncontrolled seizures
* Other clinical conditions judged non compatible with the procedure and/or the treatment
* Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA (or negative HCV RNA but on antiviral treatment) and/or Treponema Pallidum or Mycoplasma active infection
* Active alcohol or substance abuse within 6 months of the study
* Pregnancy or lactation
* Previous allogeneic bone marrow transplantation or gene therapy
* For paediatric patients only: availability of an HLA-matched donor (sibling or of a suitable 10/10 matched unrelated donor).
3 Years
64 Years
ALL
No
Sponsors
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Fondazione Telethon
OTHER
Orchard Therapeutics
INDUSTRY
IRCCS San Raffaele
OTHER
Responsible Party
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Alessandro Aiuti
Director of Pediatric Clinical Research Unit
Principal Investigators
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Alessandro Aiuti, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Ospedale San Raffaele
Fabio Ciceri, MD
Role: STUDY_CHAIR
Ospedale San Raffaele
Sarah Marktel, MD
Role: STUDY_CHAIR
Ospedale San Raffaele
Maria Domenica Cappellini, MD
Role: STUDY_CHAIR
IRCCS Policlinico Foundation
Giuliana Ferrari, PhD
Role: STUDY_DIRECTOR
Telethon Institute of Gene Therapy, Ospedale San Raffaele
Locations
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Ospedale San Raffaele
Milan, , Italy
Countries
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References
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Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013 Aug 23;341(6148):1233151. doi: 10.1126/science.1233151. Epub 2013 Jul 11.
Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest. 2007 Aug;117(8):2233-40. doi: 10.1172/JCI31666.
Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo L, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58. doi: 10.1056/NEJMoa0805817.
Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11.
Frittoli MC, Biral E, Cappelli B, Zambelli M, Roncarolo MG, Ferrari G, Ciceri F, Marktel S. Bone marrow as a source of hematopoietic stem cells for human gene therapy of beta-thalassemia. Hum Gene Ther. 2011 Apr;22(4):507-13. doi: 10.1089/hum.2010.045. Epub 2011 Mar 4.
Miccio A, Cesari R, Lotti F, Rossi C, Sanvito F, Ponzoni M, Routledge SJ, Chow CM, Antoniou MN, Ferrari G. In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia. Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10547-52. doi: 10.1073/pnas.0711666105. Epub 2008 Jul 23.
Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, Sergi Sergi L, Benedicenti F, Ambrosi A, Di Serio C, Doglioni C, von Kalle C, Naldini L. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol. 2006 Jun;24(6):687-96. doi: 10.1038/nbt1216. Epub 2006 May 28.
Roselli EA, Mezzadra R, Frittoli MC, Maruggi G, Biral E, Mavilio F, Mastropietro F, Amato A, Tonon G, Refaldi C, Cappellini MD, Andreani M, Lucarelli G, Roncarolo MG, Marktel S, Ferrari G. Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. EMBO Mol Med. 2010 Aug;2(8):315-28. doi: 10.1002/emmm.201000083.
Other Identifiers
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2014-004860-39 (EudraCT)
Identifier Type: -
Identifier Source: org_study_id
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