Lentiviral-mediated Gene Therapy of Fanconi Anemia Patients Subtype A

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Fanconi Anemia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous CD34+ cells transducted with PGK-FANCA-Wpre *<br>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)<br> <br> Biological: Genetically Engineered Hematopoietic Stem/Progenitor Cells<br>* Undergo infusion of genetically modified hematopoietic progenitor cell therapy<br>* Other names: Genetically Engineered HSPCs;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Filgrastim<br>* Given subcutaneously (SC)<br>* 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<br>* Given SC<br>* Other names: AMD 3100, JM-3100, Mozobil, SDZ SID 791;Procedure: Bone Marrow Aspiration<br> <br> |

What is the study measuring?
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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 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. | 3 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). | 3 years after infusion of transduced cells |