Work package leader : Hôpitaux de Toulouse
Lentiflash-based gene therapy (Phase I/II) for lymphedema
WP 7 objectives is to conduct the clinical pilot phase on 10 patients under using gene delivery lentiflash vector.
The first step of the WP7 will be to conduct the pre-clinical studies performed according to Good Laboratory Practices (GLP) for the submission of the clinical trial authorization to the competent authorities, i.e. the bio distribution, toxicity, acute/persistence and elimination of Lentiflash-based gene therapy after repeated injections in lymphedema rat model. The experimental design will be performed according to the European Pharmacopea 5.2.3. Animals (male and female) will be administrated with gene therapy product by injections into the limb with lymphedema under ventilation. The toxicity will be evaluated for acute study on D3 [or later depending on the peak of expression of the genes] and D90 for persistence study by analyses of haematology, blood chemistry and anatomopathology. The humoral response (IgG quantification) and the inflammation (IL-6, IL-1β, TNF-α quantification) will be evaluated for acute study. The first week after treatment, urine and blood will be collected for analysis of the elimination of transgene by RT-PCR. The biodistribution (D3 and D90) and persistence (D90) will be analysed in gonads, brain, lungs, lymph node, spleen, liver, kidneys, blood and skin of rats sacrificed at D3 and D90 by extraction of DNA and RT-PCR analysis. The results of these studies will be included in the clinical trial authorization application file submitted to ethic committee (CPP) and French medical agency (ANSM).
The pilot clinical phase of the project will evaluate first safety and feasibility of gene therapy treatment in patients with lymphedema following breast cancer treatment. The CHU of Toulouse will be the sponsor of this phase 1 study in human. The clinical center of investigation of biotherapy, which has the experience of this kind of innovative project, will be responsible for organizing multidisciplinary meetings (methodologist, statistician, clinical research assistant, and project manager) for the finalization of the study design from the pre-clinical results obtained. This pilot study will be conducted in the vascular medicine department of the Prof BURA-RIVIERE under the coordination of the CIC-BT. It will be a prospective, mono-centric, open labelled phase. Patients with lymphedema following surgery for breast cancer will be recruited and follow up in department of Vascular medicine of Toulouse University Hospital. 3 injections of LentiFlash will be realized in 10 patients at 1 interval month (D0, M1 and M2). The doses will be extrapolated from the optimal dose determined in animals during the work package 6. The follow-up visits will be at 3, 6, 9 and 12 months following the first injection (M3, M6, M9, M12):
A Data and Safety Monitoring Board (DSMB) will be organized in order to evaluate the safety of the repeated injections 3 months after the third injection (primary endpoint) for the 10 patients injected. The DSBM will be composed by independent members with expertise in relevant following clinical specialties:
- one in gene therapy,
- one in vascular medicine,
- one in vigilance and,
- one for methodological aspects
We are determined to find a treatment.