Preliminary pharmacokinetic and safety data after a single intravenous infusion of Voyager-V1 (VV1, VSV-IFNβ-NIS) oncolytic virus in patients with relapsed refractory hematologic malignancies.

Abstract

e14594 Background: Voyager-V1 (VV1) is an oncolytic vesicular stomatitis virus engineered to express interferon beta (IFNβ) to boost cellular antitumor immunity and sodium iodine symporter (NIS). A phase 1 trial investigating a single infusion of VV1 in patients with relapsed refractory multiple myeloma and T-cell lymphoma (TCL) showed promising and durable clinical activity, primarily in patients with TCL. VV1 infects tumor cells and macrophages in the lymph nodes and spleen, resulting in release of tumor antigens and IFNβ that activates and boost cellular antitumor immunity. We present the preliminary pharmacokinetic analysis in patients given one intravenous (IV) dose of VV1. Methods: Patients received 5e9 to 1.7e11 TCID50 (50% tissue culture infective dose) of VV1 given over 30 minutes. We also explored the impact of infusion duration (0.25, 0.5,1 and 3 hours) in 17 patients with solid tumors. The objectives were to determine the impact of viral dose on pharmacokinetics (PK) of VSV and IFNβ. For VSV and IFNβ PK, whole blood was collected in 30 patients on days 1, 2, 3, and 8. Dose levels were 1.7E10, 5E10, and 1.7E11 TCID50. The plasma concentration-time data were estimated with non-compartmental analysis using WinNonlin 8.3. Results: The half-life of VV1 is comparable (10-12h) between dose levels of 1.7e10, 5e10 and 1.7e11. Ideal infusion rate was found to be 30 minutes and provides the highest Cmax and AUC. Most peak concentrations for viremia and IFNβ were achieved between ‘end of infusion’ and 2.5 hours, 4.5 and 24 hours, respectively. Following infusion, a second concentration peak is found in over half the patients leading to highly variable terminal elimination half-life, specifically where the second peak is at 24 hours. There was no second peak for IFNβ levels. Peak plasma concentration and systemic exposure increased in proportion to increased dose, consistent with linear clearance. Conclusions: The 30 minute infusion rate was considered the best as its PK provides the highest Cmax and AUC with no significant CRS differences among other groups. IL-6 and IFNα markers at hour 4 indicate a likely CRS and hour 24 provides a possible prediction of the grade. Cmax and AUC were also highest at 1.7e11 TCID50. This is the recommended dose that will be used in the expansion arm in patients with TCL. Clinical trial information: NCT03017820 , NCT02923466 . [Table: see text]