Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver Journal Article
| Authors: | 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. |
| Article Title: | Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver |
| 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. © Mary Ann Liebert, Inc. |
| Keywords: | adult; cancer chemotherapy; clinical article; human tissue; treatment response; aged; middle aged; treatment failure; clinical feature; clinical trial; constipation; drug tolerability; fatigue; advanced cancer; diarrhea; dose response; drug dose comparison; drug safety; gastrointestinal hemorrhage; hypophosphatemia; liver function; side effect; liver neoplasms; protein analysis; protein blood level; metastasis; pain; cohort studies; anemia; nausea; stomatitis; vomiting; dehydration; peripheral neuropathy; deep vein thrombosis; drug screening; cancer mortality; abdominal pain; colorectal carcinoma; drug dose escalation; fever; rash; hypoxia; colorectal neoplasms; insomnia; survival time; liver; rigor; tumor necrosis factor alpha; gamma interferon; genetic engineering; gene therapy; oncolytic virus; simplexvirus; oncolytic virotherapy; infusions, intra-arterial; single drug dose; base sequence; atelectasis; skin disease; herpesvirus 1, human; anxiety; headache; phase 1 clinical trial; virus replication; dna primers; liver enzyme; gastroesophageal reflux; gamma glutamyltransferase; drug dose regimen; flatulence; alopecia; herpes simplex virus 1; nv 1020; herpes; leukocytosis; serum; tachycardia; virus detection; hepatic artery; night sweat; wound drainage; phlebitis; rhinopharyngitis; interleukin 1; gastroenteritis; virus attenuation; cold; loose feces; enzyme blood level; antibodies, viral; saliva; human herpesvirus 1; application site reaction |
| Journal Title: | Human Gene Therapy |
| Volume: | 17 |
| Issue: | 12 |
| ISSN: | 1043-0342 |
| Publisher: | Mary Ann Liebert, Inc |
| Date Published: | 2006-12-01 |
| Start Page: | 1214 |
| End Page: | 1224 |
| Language: | English |
| DOI: | 10.1089/hum.2006.17.1214 |
| PUBMED: | 17107303 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 71" - "Export Date: 4 June 2012" - "CODEN: HGTHE" - "Source: Scopus" |
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