Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A (FANCOLEN-1)

Clinical Trial Phase I / II to Evaluate the Safety and Efficacy of the Infusion of Autologous CD34 + Cells Transduced With a Lentiviral Vector Carrying the Gene FANCA in Patients With FA Subtype A (FANCOLEN-1)

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.

Study Overview

• Status: Completed
• Conditions: Fanconi Anemia
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Procedure: IV administration of Genetically Engineered Hematopoietic Stem/Progenitors Cells (HSPCs); Biological: Genetically Engineered Hematopoietic Stem/Progenitor Cells; Biological: Filgrastim; Drug: Plerixafor; Procedure: Bone Marrow Aspiration

Detailed Description

The main objective of this open-label Phase I / II clinical trial is to evaluate the safety and therapeutic efficacy of a hematopoietic gene therapy procedure with an orphan drug consisting of a lentiviral vector carrying the FANCA gene for patients with Fanconi's Anemia Subtype A.

The drug to be administered to the patients consists of the cellular product resulting from the transduction of autologous CD34 + cells with the therapeutic lentiviral vector PGK-FANCA.Wpre *.

The dose of cells to infuse in the patients will be that obtained from the transduction process of between 3x10^5 and 4x10^6 CD34 + cells / kg of patient body weight.

The cells will be infused intravenously in a single dose, after complete the transduction process.

Follow-up period: 3 years after infusion of transduced cells. However, patients will be monitored outside the clinical trial over a 10-year period.

Follow-up of the grafted transduced cells will be performed on peripheral blood and bone marrow samples.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Madrid, Spain, 28009
    • Hospital Infantil del Niño Jesus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Autologous CD34+ cells transducted with PGK-FANCA-Wpre *; 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Procedure: IV administration of Genetically Engineered Hematopoietic Stem/Progenitors Cells (HSPCs); Biological: Genetically Engineered Hematopoietic Stem/Progenitor Cells; Undergo infusion of genetically modified hematopoietic progenitor cell therapy; Other Names: Genetically Engineered HSPCs; Biological: Filgrastim; Given subcutaneously (SC); Other Names: Filgrastim XM02, Filgrastim-sndz, G-CSF (Colony Stimulating Factor), Neupogen, r-metHug-CSF, Recombinant Methionyl Human Granulocyte CSF, rG-CSF, Tbo-filgrastim, Zarxio; Drug: Plerixafor; Given SC; Other Names: AMD 3100, JM-3100, Mozobil, SDZ SID 791; Procedure: Bone Marrow Aspiration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with clinical hematological response after the infusion of autologous CD34 + cells transduced with the therapeutic lentiviral vector	Proportion of patients with clinical hematological response (improvement of cell blood counts at least in one hematological lineage).	2 years after infusion of transduced cells

Collaborators and Investigators

• Sponsor: Hospital Infantil Universitario Niño Jesús, Madrid, Spain
• Collaborators: Universitat Autonoma de Barcelona; Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz; Hospital Vall d'Hebron; Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT); Centro de Investigación en Red de Enfermedades Raras (CIBERER)
• Investigators: Study Director: Juan A Bueren, CIEMAT/CIBERER/IIS.FJD

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2016
• Primary Completion (Actual): April 23, 2019
• Study Completion (Actual): September 8, 2023

Study Registration Dates

• First Submitted: April 26, 2017
• First Submitted That Met QC Criteria: May 16, 2017
• First Posted (Actual): May 17, 2017

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Renal Tubular Transport, Inborn Errors; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Anemia; Fanconi Syndrome; Fanconi Anemia; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Immunologic Factors; Adjuvants, Immunologic; Lenograstim; Plerixafor
• Other Study ID Numbers: 2011-006100-12