Current regimens of systemic
chemotherapy result in only modest lengthening of survival in patients with advanced stage, liver-dominant, metastatic
colorectal cancer who have failed first-line
chemotherapy. The objective of this study was to investigate the safety and tolerability of NV1020, a replication-competent, attenuated, genetically engineered herpes simplex virus type 1 (HSV-1), in patients with hepatic colorectal
metastases refractory to first-line
chemotherapy. A phase I, open-label, dose-escalating study of a single 10-min hepatic arterial infusion of NV1020 in four cohorts. Three patients in each cohort received doses of 3 x 10(6), 1 x 10(7), 3 x 10(7), and 1 x 10(8) plaque-forming units. Adverse events were either mild or moderate in severity, and self-limiting. Only three serious adverse events (one transient rise in serum y-glutamyltransferase, one
diarrhea, and one
leukocytosis) experienced by three patients were considered to be possibly or probably related to NV1020. There were no deaths during the study, and there was no evidence of disseminated herpes
infection. Viral presence was detected in only one saliva sample and two serum samples from one asymptomatic patient in the highest dose cohort. In the first week after viral administration only rare and minor increases were noted for
tumor necrosis factor-alpha (six samples; three patients; peak, 40 pg/ml),
interleukin (IL)-1 (two samples; two patients; peak, 28 pg/ml), and
interferon-y (four samples; two subjects; peak, 54 pg/ml). No
IL-2 was detected. Mild liver
enzyme elevations were self-limiting and not associated with clinical symptoms. We conclude that NV1020, a genetically engineered but replication-competent HSV-1 oncolytic virus, can be safely administered into the hepatic artery without significant effects on normal liver function.