Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A

NCT03157804 | Completed Phase 1

• 1 other identifier: 2011-006100-12
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

Brief Summary

This is an open, Phase I / II clinical trial to evaluate the safety and efficacy of a hematopoietic gene therapy procedure with an orphan drug consisting of a lentiviral vector carrying the FANCA gene for patients with Fanconi Anemia of Subtype A . CD34 + cells derived from bone marrow and / or mobilized peripheral blood (fresh and / or cryopreserved) from patients with Fanconi subtype A (FA-A), will be transduced ex vivo with a lentiviral vector carrying the gene FANCA (orphan drug) . After transduction the cells will be inoculated in patients in order to restore their hematopoiesis with genetically corrected stem cells.

Conditions

Fanconi Anemia

Outcome Measures

Primary Outcomes (2)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  All adverse events will be registered for 3 years from infusion of transduced cells

  Up to 3 years after infusion of transduced cells

• Proportion of patients with at least 0.1 copy of the therapeutic vector per nucleated bone marrow or peripheral blood cells two years after infusion.

  Detection of at least 0.1 copy of the therapeutic vector per nucleated bone marrow cell or peripheral blood cells two years after infusion.

  2 years after infusion of transduced cells

Secondary Outcomes (1)

• Proportion of patients with clinical hematological response after the infusion of autologous CD34 + cells transduced with the therapeutic lentiviral vector

  2 years after infusion of transduced cells

Study Arms (1)

Autologous CD34+ cells transducted with PGK-FANCA-Wpre *

EXPERIMENTAL

CD34 + cells from patients with Fanconi subtype A (FA-A) transduced ex vivo with lentiviral vector carrying the gene FANCA, PGK-FANCA-Wpre\*The product to be infused consist of a suspension of transduced CD34\^+ cells.

Procedure: IV administration of Genetically Engineered Hematopoietic Stem/Progenitors Cells (HSPCs); Biological: Genetically Engineered Hematopoietic Stem/Progenitor Cells; Other: Laboratory Biomarker Analysis; Biological: Filgrastim; Drug: Plerixafor; Procedure: Bone Marrow Aspiration

Interventions

IV administration of Genetically Engineered Hematopoietic Stem/Progenitors Cells (HSPCs) PROCEDURE

Autologous CD34+ cells transducted with PGK-FANCA-Wpre *

Genetically Engineered Hematopoietic Stem/Progenitor Cells BIOLOGICAL

Undergo infusion of genetically modified hematopoietic progenitor cell therapy

Also known as: Genetically Engineered HSPCs

Autologous CD34+ cells transducted with PGK-FANCA-Wpre *

Laboratory Biomarker Analysis OTHER

Correlative studies

Autologous CD34+ cells transducted with PGK-FANCA-Wpre *

Filgrastim BIOLOGICAL

Given subcutaneously (SC)

Also known as: Filgrastim XM02, Filgrastim-sndz, G-CSF (Colony Stimulating Factor), Neupogen, r-metHug-CSF, Recombinant Methionyl Human Granulocyte CSF, rG-CSF, Tbo-filgrastim, Zarxio

Autologous CD34+ cells transducted with PGK-FANCA-Wpre *

Plerixafor DRUG

Given SC

Also known as: AMD 3100, JM-3100, Mozobil, SDZ SID 791

Autologous CD34+ cells transducted with PGK-FANCA-Wpre *

Bone Marrow Aspiration PROCEDURE

Autologous CD34+ cells transducted with PGK-FANCA-Wpre *

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients diagnosed with Fanconi Anemia complementation group A (FA-A)
• Minimum age 1 year
• Maximum age 21 years
• Lansky Index\> 60%.
• Informed consent in accordance with current legal regulations.
• Number of cells to be transduced: At least 3x10\^5 purified CD34+ / kg body weight.
• Negative result in the urine pregnancy test at the baseline visit for women of childbearing age, who should be committed to using an effective contraceptive method during the period of study participation.

You may not qualify if:

• Patients with an human leukocyte antigen (HLA) identical family donor.
• Evidence of myelodysplastic syndrome or leukemia, or cytogenetic abnormalities predicting the same in bone marrow aspirates. In this case, the studies carried out two months in advance of the patient's entry into the clinical trial will be considered valid.
• Evidence that the patient to be infused has signs of somatic mosaicism, with hematologic improvement.
• Any illness or concomitant process that in the opinion of the investigator incapacitates the subject for their participation in the study.
• Pre-existing sensory or motor impairment\> = grade 2 according to the National Cancer Institute (NCl) criteria.
• Pregnant or lactating women.

Sponsors & Collaborators

• Hospital Infantil Universitario Niño Jesús, Madrid, Spain: lead
• Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT): collaborator
• Centro de Investigación en Red de Enfermedades Raras (CIBERER): collaborator
• Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz: collaborator
• Hospital Vall d'Hebron: collaborator
• Universitat Autonoma de Barcelona: collaborator

Study Sites (2)

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Infantil del Niño Jesus

Madrid, 28009, Spain

Location

Related Publications (7)

• Adair JE, Sevilla J, Heredia CD, Becker PS, Kiem HP, Bueren J. Lessons Learned from Two Decades of Clinical Trial Experience in Gene Therapy for Fanconi Anemia. Curr Gene Ther. 2017;16(5):338-348. doi: 10.2174/1566523217666170119113029.

  PMID: 28103787 BACKGROUND

• Molina-Estevez FJ, Nowrouzi A, Lozano ML, Galy A, Charrier S, von Kalle C, Guenechea G, Bueren JA, Schmidt M. Lentiviral-Mediated Gene Therapy in Fanconi Anemia-A Mice Reveals Long-Term Engraftment and Continuous Turnover of Corrected HSCs. Curr Gene Ther. 2015;15(6):550-62. doi: 10.2174/1566523215666150929110903.

  PMID: 26415575 BACKGROUND

• Gonzalez-Murillo A, Lozano ML, Alvarez L, Jacome A, Almarza E, Navarro S, Segovia JC, Hanenberg H, Guenechea G, Bueren JA, Rio P. Development of lentiviral vectors with optimized transcriptional activity for the gene therapy of patients with Fanconi anemia. Hum Gene Ther. 2010 May;21(5):623-30. doi: 10.1089/hum.2009.141.

  PMID: 20001454 BACKGROUND

• Jacome A, Navarro S, Rio P, Yanez RM, Gonzalez-Murillo A, Lozano ML, Lamana ML, Sevilla J, Olive T, Diaz-Heredia C, Badell I, Estella J, Madero L, Guenechea G, Casado J, Segovia JC, Bueren JA. Lentiviral-mediated genetic correction of hematopoietic and mesenchymal progenitor cells from Fanconi anemia patients. Mol Ther. 2009 Jun;17(6):1083-92. doi: 10.1038/mt.2009.26. Epub 2009 Mar 10.

  PMID: 19277017 BACKGROUND

• Rio P, Navarro S, Guenechea G, Sanchez-Dominguez R, Lamana ML, Yanez R, Casado JA, Mehta PA, Pujol MR, Surralles J, Charrier S, Galy A, Segovia JC, Diaz de Heredia C, Sevilla J, Bueren JA. Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34+ cells from Fanconi anemia patients. Blood. 2017 Sep 28;130(13):1535-1542. doi: 10.1182/blood-2017-03-774174. Epub 2017 Aug 11.

  PMID: 28801449 BACKGROUND

• Rio P, Navarro S, Wang W, Sanchez-Dominguez R, Pujol RM, Segovia JC, Bogliolo M, Merino E, Wu N, Salgado R, Lamana ML, Yanez RM, Casado JA, Gimenez Y, Roman-Rodriguez FJ, Alvarez L, Alberquilla O, Raimbault A, Guenechea G, Lozano ML, Cerrato L, Hernando M, Galvez E, Hladun R, Giralt I, Barquinero J, Galy A, Garcia de Andoin N, Lopez R, Catala A, Schwartz JD, Surralles J, Soulier J, Schmidt M, Diaz de Heredia C, Sevilla J, Bueren JA. Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia. Nat Med. 2019 Sep;25(9):1396-1401. doi: 10.1038/s41591-019-0550-z. Epub 2019 Sep 9.

  PMID: 31501599 RESULT

• Rio P, Zubicaray J, Navarro S, Galvez E, Sanchez-Dominguez R, Nicoletti E, Sebastian E, Rothe M, Pujol R, Bogliolo M, John-Neek P, Bastone AL, Schambach A, Wang W, Schmidt M, Larcher L, Segovia JC, Yanez RM, Alberquilla O, Diez B, Fernandez-Garcia M, Garcia-Garcia L, Ramirez M, Galy A, Lefrere F, Cavazzana M, Leblanc T, Garcia de Andoin N, Lopez-Almaraz R, Catala A, Barquinero J, Rodriguez-Perales S, Rao G, Surralles J, Soulier J, Diaz-de-Heredia C, Schwartz JD, Sevilla J, Bueren JA; FANCOLEN-1 gene therapy investigators. Haematopoietic gene therapy of non-conditioned patients with Fanconi anaemia-A: results from open-label phase 1/2 (FANCOLEN-1) and long-term clinical trials. Lancet. 2025 Dec 21;404(10471):2584-2592. doi: 10.1016/S0140-6736(24)01880-4. Epub 2024 Dec 3.

  PMID: 39642902 DERIVED

MeSH Terms

Conditions

Fanconi Anemia

Interventions

Filgrastim; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; plerixafor; ferric pyrophosphate

Condition Hierarchy (Ancestors)

Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Juan A Bueren

  CIEMAT/CIBERER/IIS.FJD

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.D.PhD Specialist in Hematology Hemotherapy, Responsible for the Transfusion Service and Unit for the Obtention and Processing of Hematopoietic Progenitors and other cellular therapies at the Hospital Infantil Universitario Niño Jesús de Madrid.

Study Record Dates

• First Submitted: April 26, 2017
• First Posted: May 17, 2017
• Study Start: January 7, 2016
• Primary Completion: April 23, 2019
• Study Completion: September 8, 2023
• Last Updated: March 21, 2024

Record last verified: 2024-03

Locations

ES (2)