Vectorized gene therapy of liver tumors: proof-of-concept of TG4023 (MVA-FCU1) in combination with flucytosine. (27th September 2016)

• Record Type: Journal Article
• Authors: Husseini, F.; Delord, J.-P.; Fournel-Federico, C.; Guitton, J.; Erbs, P.; Homerin, M.; Halluard, C.; Jemming, C.; Orange, C.; Limacher, J.-M.; Kurtz, J.-E.
• Is Part Of: Annals of oncology. Volume 28:Number 1(2017)
• Page Start: 169
• Page End: 174
• Publication Date: 2016-09-27
• Subjects: vaccine -- MVA -- TG4023 -- liver tumors -- VDEPT -- suicide gene therapy; Oncology -- Periodicals; 616.992
• DOI: 10.1093/annonc/mdw440
• Languages: English
• ISSNs: 0923-7534

Abstract

Abstract: Background: TG4023 is a modified vaccinia virus Ankara (MVA) containing the yeast-originated transgene FCU1, expressing cytosine deaminase and uracil phosphoribosyltransferase enzymes that transform the prodrug flucytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluorouridine-5′-monophosphate, respectively. This first-in-human study aimed to assess the maximum tolerated dose (MTD) of intratumoral (IT) TG4023 and the safety, feasibility, and proof-of-concept (PoC) of TG4023/5-FC combination to deliver high 5-FU concentrations in tumors. Patients and methods: Cancer patients without further therapeutic option and with at least one injectable primary or metastatic liver tumor underwent on day 1 a percutaneous IT injection of TG4023 at doses of 10 7, 10 8, or 4.10 8 plaque forming units (p.f.u.) using ultrasound imaging guidance, after a dose-limiting toxicities (DLTs)-driven 3 + 3 dose-escalating design. On day 2, patients were given intravenous and/or oral 5-FC at a dose of 200 mg/kg/day for 14 days and were followed for safety through day 43. Tumor response was assessed at week 6, according to RECIST. Plasma and tumor 5-FU concentrations were measured to establish the PoC. Results: In total, 16 patients completed treatment with TG4023 and 5-FC. One DLT/7 patients (ALT/aspartate aminotransferase transient increase) was observed at 4 × 10 8 p.f.u.; MTD was therefore not reached. The most frequent adverse events were pyrexia, asthenia, vomiting, and decreased appetite. Eight of 16 patients had stable disease. Mean 5-FU concentrations in plasma were 1.9 ± 2.6 ng/ml and 56 ± 30 ng/g in tumors. Seroconversion for anti-FCU1 antibodies was found for one patient from each cohort (16%, overall). Conclusions: This phase I study demonstrated that IT injections of TG4023 were feasible and well tolerated; MTD was defined as 4 × 10 8 p.f.u. Therapeutic 5-FU concentrations in tumors established the virus-directed enzyme-prodrug therapy PoC. ClinicalTrials.gov Number: NCT00978107.