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

Primary Purpose

Fanconi Anemia

Status

Completed

Phase

Phase 1

Locations

Spain

Study Type

Interventional

Intervention

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

Genetically Engineered Hematopoietic Stem/Progenitor Cells

Laboratory Biomarker Analysis

Filgrastim

Plerixafor

Bone Marrow Aspiration

About this trial

This is an interventional treatment trial for Fanconi Anemia

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Hospital Vall d'Hebron
Hospital Infantil del Niño Jesus

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

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

Arm Description

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.

Outcomes

Primary Outcome Measures

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

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

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

Secondary Outcome Measures

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).

Full Information

NCT ID

NCT03157804

First Posted

April 26, 2017

Last Updated

September 13, 2023

Sponsor

Hospital Infantil Universitario Niño Jesús, Madrid, Spain

Collaborators

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona

1. Study Identification

Unique Protocol Identification Number

NCT03157804

Brief Title

Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A

Acronym

FANCOLEN-1

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

January 7, 2016 (Actual)

Primary Completion Date

April 23, 2019 (Actual)

Study Completion Date

September 8, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Hospital Infantil Universitario Niño Jesús, Madrid, Spain

Collaborators

4. Oversight

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Fanconi Anemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

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

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

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

Intervention Type

Biological

Intervention Name(s)

Genetically Engineered Hematopoietic Stem/Progenitor Cells

Other Intervention Name(s)

Genetically Engineered HSPCs

Intervention Description

Undergo infusion of genetically modified hematopoietic progenitor cell therapy

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Biological

Intervention Name(s)

Filgrastim

Other Intervention Name(s)

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

Intervention Description

Given subcutaneously (SC)

Intervention Type

Drug

Intervention Name(s)

Plerixafor

Other Intervention Name(s)

AMD 3100, JM-3100, Mozobil, SDZ SID 791

Intervention Description

Given SC

Intervention Type

Procedure

Intervention Name(s)

Bone Marrow Aspiration

Primary Outcome Measure Information:

Title

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

Description

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

Time Frame

Up to 3 years after infusion of transduced cells

Title

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

Description

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

Time Frame

3 years after infusion of transduced cells

Secondary Outcome Measure Information:

Title

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

Description

Proportion of patients with clinical hematological response (improvement of cell blood counts at least in one hematological lineage).

Time Frame

3 years after infusion of transduced cells

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Juan A Bueren

Organizational Affiliation

CIEMAT/CIBERER/IIS.FJD

Official's Role

Study Director

Facility Information:

Facility Name

Hospital Vall d'Hebron

City

Barcelona

ZIP/Postal Code

08035

Country

Spain

Facility Name

Hospital Infantil del Niño Jesus

City

Madrid

ZIP/Postal Code

28009

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

28103787

Citation

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.

Results Reference

background

PubMed Identifier

26415575

Citation

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.

Results Reference

background

PubMed Identifier

20001454

Citation

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.

Results Reference

background

PubMed Identifier

19277017

Citation

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.

Results Reference

background

PubMed Identifier

28801449

Citation

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.

Results Reference

background

PubMed Identifier

31501599

Citation

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.

Results Reference

result

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Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A

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