A phase II trial of JX-594, a targeted multimechanistic oncolytic vaccinia virus, followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC).

Abstract

e14566 Background: JX-594 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 (Reviewed in Nat Rev Cancer 2009). JX-594 was well-tolerated intravenously (IV) (Nature 2011) and intratumorally (IT) (Lancet Oncol 2008). Complementary anti-tumor effects are predicted with JX-594 followed by sorafenib due to acute vascular disruption effects with JX-594 and anti-angiogenic effects with sorafenib. Methods: Treatment-refractory HCC patients received JX-594 for three weeks (Day 1 IV, Day 8 IT and Day 22 IT) followed by sorafenib. An IT boost dose of JX-594 at Week 12 was optional. The primary objective of the study was to determine the safety of JX-594 followed by sorafenib in patients with advanced HCC. Secondary objectives include disease control rate (DCR) based on mRECIST and/or Choi response criteria at Day 6 (optional), Day 25 (after JX-594 only), 6 and 12 weeks. Results: Twenty (20) patients were treated in this study; fifteen (15) were refractory to sorafenib. The sequential treatment regimen was well-tolerated. Transient flu-like symptoms (Grade 1-2) and transient leukopenia (lymphopenia, neutropenia) were the most common adverse events following JX-594 therapy. Sorafenib toxicities were consistent with the expected toxicity profile. At the time of this interim analysis, thirteen patients were evaluable for radiographic response by Choi criteria (mRECIST pending). After JX-594 alone at Day 25, 10 of 13 evaluable patients (77%) had Choi tumor responses (range 19-48% reduced enhancement). Following subsequent sorafenib therapy, 11 of 13 patients (85%) had Choi responses at Week 6-12, including 9 of 10 (90%) sorafenib-failure patients. Conclusions: JX-594 was well-tolerated and associated with Choi tumor responses following IV and IT injections in patients with advanced HCC. Subsequent sorafenib was associated with the expected toxicity profile. Further trials of JX-594 in HCC patients are warranted.