title: Phase 1 clinical experience using intravenous administration of PV701, an oncolytic Newcastle disease virus.
abstract: PV701 is a naturally-attenuated, non-recombinant, oncolytic strain of Newcastle disease virus that displays preclinical intravenous (IV) efficacy. PV701 is selective at killing human cancer cells versus normal human cells based on tumor specific defects in the interferon (IFN)-mediated antiviral response. This oncolytic virus displays a broad spectrum of antitumor activity in vitro and in vivo. Preclinical models successfully predicted key clinical parameters including the mechanism of toxicity, two complementary strategies (desensitization and slow infusion) to reduce toxicity, and the starting dose for phase 1 trials. In three phase 1 trials of 114 patients using IV administration of PV701, Wellstat Biologics Corporation has evaluated the effects of dose, schedule, and infusion rate for PV701. Three general classes of side effects were seen: flu-like symptoms; tumor-site-specific adverse events (AEs); and infusion reactions. The first PV701 dose desensitized the patient to the side effects of further doses, allowing a marked increase in the maximum tolerated dose for subsequent doses compared to the first dose. Tumor responses were first noted at the higher doses achieved using desensitization. In the most recent phase 1 trial of 19 patients at Hamilton, Ontario, that employed desensitization, high repeat doses, and a slower infusion rate (Hamilton Regimen), there were six responses (4 major; 2 minor) and a total of six patients with survival for at least 2 years. In addition, patient tolerability improved using the Hamilton Regimen compared to IV bolus dosing used previously. Phase 2 studies of this novel biologic agent are about to begin.
authors.affiliation: Wellstat Biologics Corporation, Gaithersburg, MD 20878, USA. rlorence@wellstatbiologics.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lorence
authors.forename: M Scot
authors.initials: MS
authors.lastname: Roberts
authors.forename: James D
authors.initials: JD
authors.lastname: O'Neil
authors.forename: William S
authors.initials: WS
authors.lastname: Groene
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Miller
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Mueller
authors.forename: Michael K
authors.initials: MK
authors.lastname: Bamat
mesh_terms: D000818:Animals; D017321:Clinical Trials, Phase I as Topic / Q000379:methods; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D009369:Neoplasms / Q000628:therapy*; D009522:Newcastle disease virus / Q000235:genetics / Q000502:physiology; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D012107:Research Design; D016896:Treatment Outcome; D014779:Virus Replication