FANCA Gene Transfer for Fanconi Anemia Using a High-safety, High-efficiency, Self-inactivating Lentiviral Vector

Study Overview
=================
Brief Summary
-----------------
This is a Phase I/II clinical trial of gene therapy for treating Fanconi anemia using a self-inactivating lentiviral vector to functionally correct the defective gene. The objectives are to evaluate the safety and efficacy of the gene transfer clinical protocol.

Detailed Description
-----------------
Fanconi anemia is a rare, inherited disease that is caused by a gene defect and that primarily affects an individual's bone marrow, resulting in decreased production of blood cells. The major problem for most patients is aplastic anemia, the blood counts for red blood cells, white blood cells, and platelets are low. In addition, some patients have physical defects usually involving the skeleton and kidneys. Fanconi anemia is typically diagnosed in childhood, and there is a high fatality rate. Hematopoietic stem cell transplantation (HSCT) is a common treatment for Fanconi anemia. However, there are many risks associated with HSCT including rejection of the transplanted cells and graft-versus-host disease. The primary objectives are to evaluate the safety of the self-inactivating lentiviral vector, the ex vivo gene transfer clinical protocol and the efficacy of immune reconstitution in patients overcoming immune abnormalities present at the time of treatment, assessment of gene correction efficiency, and finally the long-term correction of Fanconi anemia associated disease symptoms.

Official Title
-----------------
Gene Transfer for Fanconi Anemia Using a Self-inactivating Lentiviral Vector

Conditions
-----------------
Fanconi Anemia

Intervention / Treatment
-----------------
* Genetic: Gene-modified autologous stem cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of Fanconi anemia FANCA type based on DNA sequencing and sensitivity test for chromosomal cleavage by mitomycin C or butylene oxide. No cytogenetic abnormalities and the proportion of myelodysplastic abnormalities does not exceed 5% within 3 months prior to stem cell collection. Age: ≥ 4 years. Karnofsky: ≥ 70%. ANC ≥ 5×10^8/L; PLT ≥ 2×10^10/L. Hemoglobin ≥ 8g/dL. Proper renal and hepatic functions (ULN denotes upper limit of normal range) with serum creatinine ≤ 1.5×ULN; serum bilirubin ≤ 3×ULN; AST/ALT ≤ 5×ULN. Pulmonary function is normal; DLCO > 50%. Written, informed consent obtained prior to any study-specific procedures. Exclusion Criteria: Diagnosis of active malignant disease or myelodysplastic syndrome. Diagnosis of myeloid leukemia. Pregnant or lactating females. Existence of an available HLA-identical related donor. Subject infected with HBV (HBsAg positive), HIV (HIV antibody positive), HTLV (HTLV antibody positive), Treponema pallidum antibody positive or TB culture positive. Patients, in the opinion of investigators, may not be eligible or not able to comply with the study.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gene-modified autologous stem cells<br>Autologous hematopoeitic stem cells and mesenchymal stem cells transduced with lentiviral vector carrying the FANCA gene ex vivo | Genetic: Gene-modified autologous stem cells<br>* Infusion for 5x10^6 1x10^7 per kilogram of body weight of gene-modified cells; or more infusions depending on the circumstances<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety in patients using CTCAE version 4.0 standard to evaluate the level of adverse events | Physiological parameter (measuring cytokine response, fever, symptoms) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment responses | Blood routine indexes will be obtained before and after treatment. Objective response, such as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria | 1 year | 
| Quality of life | Quality of life will be measured using the Functional Assessment of Cancer Therapy-General (FACT-G) before and after treatment. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Fanconi anemia, Lentiviral vector, FANCA, Gene