A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization

Purpose: In a previous phase 1 study, adverse events, especially flu-like symptoms, were observed mainly following the first i.v. bolus dose of PV701, an oncolytic Newcastle disease virus. Desensitization to adverse events of subsequent doses occurred, allowing a 10-fold increase in the maximum tolerated dose for these doses. Although one-step desensitization (a single desensitizing dose with higher subsequent doses) addressed the tolerability of high repeat doses, additional testing was required to further improve tolerability of the initial dose. This study tested the hypothesis that two-step desensitization, using two dose increments before high repeat doses, would be well tolerated. Experimental Design: Sixteen adults with incurable solid tumors were enrolled. Cycles consisted of six PV701 doses over 2 weeks followed by a 1-week rest. Doses 1 to 2 were 1 and 2 12 x 10(9) plaque-forming units (pfu)/m(2), respectively, whereas doses 3 to 6 were escalated by 2 cohort from 24 to 120 x 10(9) pfu/m(2). Results: No dose-limiting toxicities were observed, permitting dose escalation through cohort 4 (1, 12,120,120,120,120 x 10(9) pfu/m(2)). Mild flu-like symptoms were common following the first infusion, diminished with repeated dosing, and were less pronounced than those seen previously. Tumor regression was observed in a patient with anal carcinoma who enrolled with stable disease following palliative radiotherapy. Four patients with clearly progressing cancer before enrollment had disease stabilization of >= 6 months. Conclusions: This novel two-step desensitization improved patient tolerability compared with the previous regimen. Toxicities were predictable and manageable. PV701, the first oncolytic virus to enter phase 1 i.v. testing, continues to show single-agent activity, warranting planned phase 2 trials.