Proof of Concept of Gene Therapy Using Plasmid Amep in Disseminated Melanoma: Safety and Efficacy Results of A Phase I First-In-Man Study

ABSTRACT Background AMEP (for Antiangiogenic MEtargidin Peptide) is a novel anti-cancer agent with proven anti-proliferative and anti-angiogenic properties by binding of avb3 and a5b1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues, and is an attractive alternative to viral gene therapy. This study investigated safety and tolerability of intratumoural plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Patients and methods Five pts with disseminated melanoma without further treatment options (median age 62 y, AJCC IIIC/IV, ECOG status ≤2) were treated at two dose levels (1 and 2 mg DNA) in a phase I study. In each patient, two cutaneous lesions were identified (one treated, one control). Under local anaesthesia, at day 1 and day 8, plasmid AMEP was injected intratumourally followed by electrotransfer with needle electrodes. Pts were monitored weekly until day 29, and at day 64. At day 29 local efficacy was assessed by measuring both lesions and post-treatment biopsies were obtained for determination of AMEP mRNA levels by RT-QPCR. Pharmacokinetic evaluation of plasmid AMEP by QPCR was performed on plasma and urine. Results The 5 pts received the 2 planned injections. Minimal systemic toxicity was observed including transient fever (1 pt) and transitory increase in C-Reactive Protein (2 pts). Local toxicity after injection was reported as mild. No related serious adverse events were seen. AMEP mRNA was found in 3 of 5 treated lesions and none of control lesions. Plasmid AMEP was detected in plasma in 4 of 5 pts, but not in urine. At day 29, all 5 treated lesions were stable in diameter, whereas 4 of 5 control lesions increased over 20 %. Response was not observed in any distant lesions. Conclusion This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma tumours shows local efficacy, efficiency of the DNA transfer method as well as an excellent safety profile. Further studies using the intramuscular route will evaluate whether a systemic efficacy of plasmid AMEP could be obtained using this transfer method. Disclosure C. Bouquet: Employee and stockholder at BioAlliance Pharma, who sponsored the study B. Vasseur: Employee at BioAlliance Pharma, who sponsored the study P. Attali: Employee and stockholder at BioAlliance Pharma who sponsored the study All other authors have declared no conflicts of interest.