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TPS4161^ Background: Pexa-Vec is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony stimulating factor (GM-CSF). Direct oncolysis plus GM-CSF expression stimulates tumor vascular disruption and anti-tumor immunity (Nature Rev Cancer, 2009). Pexa-Vec was well-tolerated in Phase 1 trials and was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol, 2008 and Nature, 2011). A randomized high vs low dose Phase 2 trial in 30 patients with advanced HCC, demonstrated prolonged survival in the high-dose Pexa-Vec arm (median survival 14.1 mo vs. 6.7 mo; Hazard Ratio 0.39, p=0.02) (AASLD Annual Meeting, 2011, LB1). Methods: TRAVERSE is a Phase 2b randomized, open-label, multi-center trial in patients with advanced HCC who have failed sorafenib treatment. Approximately 120 patients will be randomized 2:1 to Pexa-Vec plus BSC versus BSC, respectively. Randomization will be stratified by region (Asian vs. non-Asian); sorafenib intolerant vs refractory; and presence vs absence of extra-hepatic disease. The primary objective is to determine overall survival. Main inclusion criteria are advanced HCC having failed sorafenib (intolerance or radiographic progression during or < 3 months following last sorafenib), Child-Pugh A-B7 (no ascites), acceptable hematologic function. Assuming a median overall survival of 4.0 months with BSC and a target hazard ratio of 0.57 (corresponding to an experimental arm median survival of 7.0 months), 73 events (deaths) will provide 70% power at 1-sided alpha = 0.05 to detect a difference in overall survival between the treatment groups using a stratified logrank test. Patients randomized to Pexa-Vec will receive a dose of 109 plaque forming units (pfu) IV on Day 1 followed by five IT treatments between Day 8 and Week 18. Enrollment has begun on this study with clinical trial registry number of NCT01387555. Clinical trial information: NCT01387555.

14094 Background: HCC is a highly chemoresistant due to MDR efflux pumps. DT is a newly cytotoxic chemotherapy composed of doxorubicin-loadded polyisohexylcyanoacrylate nanoparticles, allowing doxorubicin to overcome MDR pumps [Barraud, J Hepatol 2005; 42: 736]. Methods: 16 cirrhotic patients (pts) of Child-Pugh A with advanced HCC, transaminases/GGT 100000/mm3, neutrophiles >1500/mm3, were enrolled in a multicentric noncontrolled study. A single IAH injection of 10, 20, 30, 35, or 40mg/m2 DT (respectively 3,3,4, and 3 pts) was performed, tolerance and efficacy being assessed 4 weeks later. Results: Grade 4 neutropenia (2pts at 40mg/m2) gave the Maximal Tolerated Dose. Grade 2–3 hypertransaminasemia (transient) occurred dose-independently. Two serious adverse events (SAE) were hypotension and acute respiratory distress syndrome. All adverse events (AE) (90% grade 1–2) occurring during injection were dose-independent, and completely and fastly recovered : cough (6pts), dyspnea (2pts), SaO2 decrease (2pts), tachycardia (2pts), bradycardia (2pts), hypotension (2pts). Anti-tumor efficacy of DT was evaluated by helicoidal CT-scan with contrast injection 4 weeks after injection : 3pts (20%) showed partial response with frank decrease of contrast enhancement at arterial perfusion, 8pts (50%) remained stable, and 5pts (30%) had progression. Conclusions: This phase 1 showed that a single IAH injection of DT was safe until 35 mg/m2 for Child-Pugh A patients with advanced HCC. This dosage will be retained for the phase 2 step comprising 3 injections at 4-week intervals which will aim at confirming the antitumour efficacy of DT for HCC. [Table: see text]