Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers

Purpose: PV701, a replication-competent strain of Newcastle disease virus, causes regression of tumor xenografts after intravenous administration. This phase I study was designed to define the maximum-tolerated dose (MTD) and safety of single and multiple intravenous doses of PV701 as a single agent in patients with cancer. Patients and Methods: Seventy-nine patients with advanced solid cancers that were unresponsive to standard therapy were enrolled. Four PV701 intravenous dosing regimens were evaluated: (1) single dose: one dose every 28 days; (2) repeat dose: three doses in 1 week every 28 days; (3) desensitizing: one lower dose followed by two higher doses in 1 week every 28 days; and (4) two week: one lower dose followed by five higher doses over 2 weeks every 21 days. Results: A 100-fold dose intensification was achieved over 195 cycles. A first-dose MTD of 12 × 10⁹ plaque-forming units (PFU)/m² was established for outpatient dosing. After an initial dose of 12 × 10⁹ PFU/m², patients tolerated an MTD for subsequent doses of 120 × 10⁹ PFU/m². The most common adverse events were flu-like symptoms that occurred principally after the first dose and were decreased in number and severity with each subsequent dose. Tumor site-specific adverse events and acute dosing reactions were also observed but not cumulative toxicity. Objective responses occurred at higher dose levels, and progression-free survival ranged from 4 to 31 months. Tumor tissue from one patient was obtained after 11 months of therapy and showed evidence of PV701 particles budding from the tumor cell membrane by electron microscopy and a pronounced lymphoplasmacytic infiltrate by histologic examination. Conclusion: PV701 warrants further study as a novel therapeutic agent for cancer patients.