Gene Therapy for Transfusion Dependent Beta-thalassemia

NCT02453477 | Unknown Phase 1 DMC

• 1 other identifier: 2014-004860-39 (EudraCT)
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene for the treatment of patients affected by transfusion dependent beta-thalassemia

Conditions

Beta-Thalassemia

Keywords

Beta thalassemia; Gene therapy; Lentiviral vector

Outcome Measures

Primary Outcomes (7)

• Overall survival

  Number of patients alive all over the trial

  2 years

• Achievement of hematological engraftment

  Haematological engraftment is defined as first day of neutrophil count \>500/mm3 and platelets \>20,000/mm3 on 3 consecutive blood counts.

  within day +60 after gene therapy

• Safety of the administration of autologous haematopoietic stem cells transduced with LV-GLOBE

  * short-term tolerability: the percentage of patients not experiencing short-term (0-24 hours from injection) adverse events (of any grade) and systemic reactions. * absence of Replication Competent Lentivirus (RCL): the percentage of subjects without RCL in the 24 months from injection. * absence of abnormal clonal proliferation: the percentage of subjects without abnormal clonal proliferation in the 24 months from injection.

  0-24 months after gene therapy

• Short-term safety and tolerability of the different conditioning regimens

  The percentage of patients with the following clinical events from day -5 to +100 days from injection: NCI (National Cancer Institute Common Terminology Criteria grading) ≥2 and metabolic/laboratory NCI ≥3.

  from day -5 (first day of conditioning treatment) to day 100 after gene therapy

• Overall safety and tolerability measured by AE recording

  The number of AEs (adverse events) and SAEs (serious adverse events) and the percentage of subjects experiencing AEs and SAEs in the 24 months post injection will be summarized by severity and within body system involved.

  0-24 months after gene therapy

• Polyclonal engraftment

  The percentage of subjects with polyclonality of haematopoiesis will be estimated at 6, 12, 18 and 24 months from injection. Polyclonality of haematopoiesis will be defined as \> 1000 unique integration sites retrieved from peripheral blood and/or bone marrow cells.

  From 6 months to 2 years after gene therapy

• Reduction in transfusion frequency up to transfusion independence

  Transfusions will be recorded as mLs of blood/kg/months

  from -7 months before gene therapy to 2 years after gene therapy

Secondary Outcomes (5)

• Transfusion independence

  9 months, 1, 1.5 and 2 years after gene therapy

• Adequate haemoglobin level

  0-24 months after gene therapy

• Adequate engraftment of genetically corrected cells

  6, 12, and 24 months after gene therapy

• Transgene expression

  6, 12, and 24 months after gene therapy

• Improvement of health-related quality of life

  12 and 24 months

Study Arms (3)

Adults

EXPERIMENTAL

≥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.

Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene

Elderly children

EXPERIMENTAL

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.

Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene

Younger children

EXPERIMENTAL

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.

Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene

Interventions

Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene GENETIC

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.

Adults; Elderly children; Younger children

Eligibility Criteria

• Age: 3 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Written informed consent
• 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

You may not qualify if:

• Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
• 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).

Sponsors & Collaborators

• IRCCS San Raffaele: lead
• Fondazione Telethon: collaborator
• Orchard Therapeutics: collaborator

Study Sites (1)

Ospedale San Raffaele

Milan, 20132, Italy

Location

Related Publications (8)

• 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.

  PMID: 23845947 BACKGROUND

• 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.

  PMID: 17671653 BACKGROUND

• 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.

  PMID: 19179314 BACKGROUND

• 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.

  PMID: 23845948 BACKGROUND

• 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.

  PMID: 20979441 BACKGROUND

• 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.

  PMID: 18650378 BACKGROUND

• 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.

  PMID: 16732270 BACKGROUND

• 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.

  PMID: 20665635 BACKGROUND

MeSH Terms

Conditions

beta-Thalassemia

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Alessandro Aiuti, MD, PhD

  Ospedale San Raffaele

  PRINCIPAL INVESTIGATOR

• Fabio Ciceri, MD

  Ospedale San Raffaele

  STUDY CHAIR

• Sarah Marktel, MD

  Ospedale San Raffaele

  STUDY CHAIR

• Maria Domenica Cappellini, MD

  IRCCS Policlinico Foundation

  STUDY CHAIR

• Giuliana Ferrari, PhD

  Telethon Institute of Gene Therapy, Ospedale San Raffaele

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Pediatric Clinical Research Unit

Study Record Dates

• First Submitted: May 15, 2015
• First Posted: May 25, 2015
• Study Start: May 1, 2015
• Primary Completion: August 1, 2019
• Study Completion: August 1, 2019
• Last Updated: June 28, 2019

Record last verified: 2019-06

Locations

IT (1)