183: Pharmacokinetics & Viral Shedding of an Oncolytic Virus (MEDI5395) in a Phase 1 Clinical Study

Statement of Purpose: MEDI5395 (NDV-hGM-CSF) is a Newcastle Disease Virus (NDV)-based oncolytic virus incorporating human granulocyte-macrophage colony-stimulating factor (GM-CSF) that has successfully entered first-in-human clinical trials. Herein, we report the pharmacokinetics (PK), NDV neutralizing antibody (nAb), and viral shedding results from a Phase 1 dose-escalation study of MEDI5395 in patients with advanced solid tumors (NCT03889275).

Description of Methods & Materials: Four dose levels of MEDI5395 were evaluated for PK, nAb, and viral shedding. Multiple doses of MEDI5395 (six doses over 2 weeks) were administered via intravenous infusion in combination with sequential or concurrent durvalumab. Whole blood samples were analyzed for viral genome copies using a real-time quantitative polymerase chain reaction (RT-qPCR) assay to assess MEDI5395 PK. GM-CSF levels in plasma were detected using a Meso Scale Discovery (MSD) immunoassay to assess transgene expression. Viral shedding in saliva and urine were assessed by viral genome RT-qPCR as well as a cell-based infectivity assay. Virus-induced neutralizing antibody titers were analyzed by a cell-based viral microneutralization assay.

Data & Results: A total of 39 participants received 6 infusions of MEDI5395 over a period of 2 weeks, at up to 4 ascending dose levels. A tendency towards dose-dependent PK of the NDV genome was observed in whole blood following repeat MEDI5395 administration, with the median peak time (T_max) observed between the second and sixth dose. No dose proportionality was observed at any dose levels tested. The PK profiles for MEDI5395 were generally comparable when combined with durvalumab sequentially or concurrently. Exposure to the MEDI5395 viral genome lasted approximately 13 to 51 days and increased with increasing dose level. Plasma GM-CSF levels were slightly elevated in participants from the two higher dose cohorts at the end of infusion. A tendency towards dose-dependent viral shedding was observed in saliva and urine following repeat administration of MEDI5395 alone or concurrently with durvalumab. The median T_max for viral shedding in saliva was generally observed between the first and fourth dose, while the median T_max for viral shedding in urine was observed after the sixth dose, with a range of 17 to 24 days after the first dose. The presence of viruses in saliva and urine was detected over a duration of approximately 8 to 17 days and 4 to 15 days, respectively. Infectious viruses excreted through saliva and urine were found at low titers in the RT-qPCR quantifiable samples. The NDV nAb was detected as early as 9 days post MEDI5395 administration but did not cause a decrease in viremia during repeat dosing.

Interpretation, Conclusion or Significance: MEDI5395 exhibited dose-dependent PK and viral shedding, with indication of viral replication and GM-CSF expression. The small number of infectious saliva and urine samples indicates that environmental safety is of little concern.

Disclosures: CF, ZC, ND, ET, JC, FA, SR, MG, AP are current employees of and shareholders in AstraZeneca.