A phase Ib trial of JX-594 (Pexa-Vec), a targeted multimechanistic oncolytic vaccinia virus, in combination with low-dose cyclophosphamide in patients with advanced solid tumors

Abstract

Background: JX-594 (Pexa-Vec) is a targeted oncolytic vaccinia virus designed to selectively replicate in and destroy cancer cells with epidermal growth factor receptor (EGFR)/ras pathway activation. Direct oncolysis plus GM-CSF expression is accompanied by tumor vascular disruption and anti-tumoral immunity. JX-594 was welltolerated intravenously (IV) and intratumorally (IT). Given the immunomodulatory effects of low-dose cyclophosphamide (CP), anti-tumor synergy is predicted with JX- 594. Methods: CP was delivered orally at the dose of 50 mg BID one week on one week off. JX-594 was delivered IV at day 8 of each day 28-cycle. 2 dose levels of JX-594 were explored: 3.108 and 1.109 plaque forming units (pfu). The primary objective of the study was to determine the safety of JX-594 in combination with low-dose CP in patients with advanced solid tumors. Secondary objectives include response rates, PFS, pharmacokinetics and pharmacodynamics. Results: Ten patients entered the study. 9 were evaluable for safety. No dose limiting toxicity was observed. The combination regimen was well-tolerated. The most frequent adverse events were grade 1-2 fever/transient flu-like symptoms (n=10), grade 1-2 nausea (n=5), grade 1-2 anemia (n=4) and grade 1-2 fatigue (n=4). 2 patients (breast cancer, ovarian cancer) had stable disease as best overall response. Conclusions: IV JX-594 was well-tolerated in combination with low-dose CP. PK and PD (immunological profiling) will be presented at the meeting. Two phase 2 studies are ongoing in patients with advanced HER2 negative breast cancer and advanced softtissue sarcomas, respectively.