title: Gene electrotransfer of plasmid antiangiogenic metargidin peptide (AMEP) in disseminated melanoma: safety and efficacy results of a phase I first-in-man study.
abstract: Antiangiogenic metargidin peptide (AMEP) is a novel anticancer agent exerting antiproliferative and antiangiogenic effects by binding to αvβ3 and α5β1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I study investigated safety and tolerability of intratumoral plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA). In each patient, two cutaneous lesions were identified (one treated and one control). At day 1 and day 8, plasmid AMEP was injected intratumorally followed by electrotransfer. Patients were monitored weekly until day 29, and at day 64. Local efficacy was assessed at day 29 by direct measurement, and posttreatment biopsies for AMEP mRNA levels were evaluated by reverse transcriptase quantitative polymerase chain reaction. Plasmid copy number in blood and urine was determined by quantitative polymerase chain reaction. Minimal systemic toxicity was observed, including transient fever and transitory increase in C-reactive protein. No related serious adverse events occurred. Plasmid AMEP was detected in plasma but not in urine. AMEP mRNA was found in three of five treated lesions and none of the control lesions. At day 29, all five treated lesions were stable in diameter, whereas four of five control lesions increased more than 20%. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe and that local transfection was obtained.
authors: 1 Department of Oncology, Center for Experimental Drug and Gene Electrotransfer, Copenhagen University Hospital Herlev , Herlev 2730, Denmark .
authors: Iben
authors: I
authors: Spanggaard
authors: Marko
authors: M
authors: Snoj
authors: Andrea
authors: A
authors: Cavalcanti
authors: Céline
authors: C
authors: Bouquet
authors: Gregor
authors: G
authors: Sersa
authors: Caroline
authors: C
authors: Robert
authors: Maja
authors: M
authors: Cemazar
authors: Elisabeth
authors: E
authors: Dam
authors: Bérangère
authors: B
authors: Vasseur
authors: Pierre
authors: P
authors: Attali
authors: Lluis M
authors: LM
authors: Mir
authors: Julie
authors: J
authors: Gehl
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018274:Electroporation; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D006801:Humans; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010957:Plasmids / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000628:therapy*; D014162:Transfection / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; D051722:ADAM Proteins; C098660:ADAM15 protein, human