Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver

Nancy Kemeny, Karen Brown, Anne Covey, Teresa Kim, Amit Bhargava, Lynn Brody, Brenda Guilfoyle, Natasha P. Haag, Matthias Karrasch, Birgit Glasschroeder, Anette Knoll, George Getrajdman, K. Jon Kowal, William R. Jarnagin, Yuman Fong

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

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 × 106,1 × 107, 3 × 107, and 1 × 108 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 γ-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-α (six samples; three patients; peak, 40 pg/ml), interleukin (IL)-1 (two samples; two patients; peak, 28 pg/ml), and interferon-γ (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.

Original languageEnglish (US)
Pages (from-to)1214-1224
Number of pages11
JournalHuman Gene Therapy
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Kemeny, N., Brown, K., Covey, A., Kim, T., Bhargava, A., Brody, L., Guilfoyle, B., Haag, N. P., Karrasch, M., Glasschroeder, B., Knoll, A., Getrajdman, G., Kowal, K. J., Jarnagin, W. R., & Fong, Y. (2006). Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver. Human Gene Therapy, 17(12), 1214-1224. https://doi.org/10.1089/hum.2006.17.1214