A phase I clinical trial of a genetically modified and imageable oncolytic vaccinia virus GL-ONC1 with clinical green fluorescent protein (GFP) imaging.

Abstract

2577 Background: GL-ONC1 is a genetically engineered vaccinia virus attenuated by insertion of the ruc-gfp (Renilla luciferase and Aequorea green fluorescent protein fusion gene), beta-galactosidase (lacZ) and beta-glucuronidase (gusA) reporter genes into the F14.5L, J2R (thymidine kinase) and A56R (hemagglutinin) loci, respectively. A Phase I trial of intravenous GL-ONC1 was pursued to evaluate safety, tolerability, tumour delivery, neutralizing antibody development and anti tumour activity. Methods: GL-ONC1 was to be administered at escalating doses (1×105, 1×106, 1×107, 1×108, 1×109, 3×109 plaque-forming units (pfu) on day 1 only; 1.667×107 and 1.667×108 pfu on day 1-3; 1×109 pfu on day 1-5) using a 3+3 dose escalation design and a q28 days schedule. GFP imaging was performed at baseline and after each cycle on superficial and mucosal lesions. Results: To date, 21 patients (males 15, median age 57 years) have been treated without dose limiting toxicities. Adverse events reported were generally mild (grade 1/2) and included pyrexia (n:8), fatigue (n:4), myalgia (n:3), pustular rash (n:2), hypotension (n:2), nausea (n:2), tachycardia (n:2), anorexia (n:1), diarrhoea (n:1), hyperhidrosis (n:1), oedema (n:1), rhinorrhea (n:1), rigor (n:1), seborrhoea (n:1), thrombocytosis (n:1), flank pain (n:1), feet plantar tenderness (n:1), back pain (n:1) calf pain (n:1) and vomiting (n:1). One patient suffered a left common femoral artery embolism of uncertain causality (grade 3). Two patients had a pustular rash, 1 asymptomatic (grade 1) and 1 symptomatic with itching (grade 2). Both appeared during the first week of treatment with green fluorescence on GFP imaging and positivity by viral plaque assay (VPA) and resolved spontaneously by the end of cycle 1. VPA of blood, urine, stool and sputum were negative for viral shedding in all but 1 patient who had positive shedding for 11 days. Increased neutralizing antibody titres were seen in all tested patients except 1. Best response was RECIST stable disease > 6 months (n:1) and 3-6 months (n:5). Conclusions: GL-ONC1 can be administered intravenously, is well tolerated and its delivery can be imaged in cancer patients.