Clinical trial NCT03157804: Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A
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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Fanconi Anemia
Lead sponsor: Hospital Infantil Universitario Niño Jesús, Madrid, Spain
Sponsor class: OTHER
Collaborators: name: Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)
name: Centro de Investigación en Red de Enfermedades Raras (CIBERER)
name: Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
name: Hospital Vall d'Hebron
name: Universitat Autonoma de Barcelona
First posted: 2017-05-17
Enrollment: 9
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: Up to 3 years after infusion of transduced cells
measure: 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.
timeFrame: 2 years after infusion of transduced cells
Secondary outcomes:
measure: Proportion of patients with clinical hematological response after the infusion of autologous CD34 + cells transduced with the therapeutic lentiviral vector
timeFrame: 2 years after infusion of transduced cells
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Infantil del Niño Jesus
Study officials:
affiliation: CIEMAT/CIBERER/IIS.FJD
name: Juan A Bueren
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.
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.
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.