A Study of Pexa-Vec (JX-594) Prior to Sorafenib to Treat Unresectable Primary Hepatocellular Carcinoma

A Phase 2 Open-Label Pilot Safety Study of JX-594 Administered by IV Infusion Followed by Intratumoral Injection Prior to Standard Sorafenib Treatment in Patients With Unresectable Primary Hepatocellular Carcinoma

The purpose of this pilot safety study is to evaluate the safety and tolerability of JX-594 (Pexa-Vec) administered intravenously and intratumorally prior to standard sorafenib therapy.

This is a Phase 2, open-label, pilot safety study designed to evaluate the safety and tolerability of sequential therapy consisting of Pexa-Vec (JX-594) followed by standard sorafenib in patients with advanced, unresectable primary hepatocellular carcinoma (HCC).

Patients will receive an initial intravenous (IV) infusion of Pexa-Vec at a dose of 1 x 10^9 plaque-forming units (pfu) on Day 1. This is followed by two intratumoral (IT) injections of Pexa-Vec on Day 8 and Day 22, each at a total dose of 1 x 10^9 pfu divided among 1 to 5 hepatic tumors. Starting on Day 25 (approximately 3 days after the final regular dose of Pexa-Vec), patients will initiate standard oral sorafenib therapy twice daily. For patients with viable hepatic tumor tissue at Week 12, an optional additional IT dose of Pexa-Vec may be administered.

The primary objective of this study is to assess the safety and toxicity of this sequential regimen, determined by the incidence of treatment-related Grade 3 and Grade 4 adverse events (AEs) and treatment-related serious adverse events (SAEs). Secondary objectives include evaluating the disease control rate (DCR) at 12 weeks, overall survival (OS) time, and radiographic response rate based on modified RECIST (mRECIST 1.0) and/or Choi criteria.

Inclusion Criteria:

• Histological confirmation or clinical/laboratory diagnosis of primary hepatocellular carcinoma (HCC)
• Cancer is not surgically resectable for cure
• Child Pugh A or B
• Performance Score: KPS score of ≥ 70
• Platelet count ≥ 50,000 plts/mm3
• Total bilirubin ≤ 2.5 x ULN
• AST, ALT < 5.0 x ULN
• Acceptable coagulation status: INR ≤ 1.5 x ULN
• Acceptable kidney function: Serum creatinine < 2.0 mg/dL
• Sorafenib naive or refractory to sorafenib therapy Tumor Status: At least one intrahepatic tumor, and at least ≥50% of the total intrahepatic viable tumor mass, measurable by CT and injectable under imaging-guidance (note: injected and/or viable tumors must be previously untreated or ≥20% increase in size since preceding local-regional treatment).

Exclusion Criteria:

• Known contraindications to sorafenib
• Pregnant or nursing an infant
• Significant immunodeficiency due to underlying illness (e.g. hematological malignancies, congenital immunodeficiencies and/or HIV infection/AIDS) and/or medication (e.g. high-dose systemic corticosteroids)
• History of exfoliative skin condition (e.g. severe eczema, ectopic dermatitis, or similar skin disorder) that at some stage has required systemic therapy
• Clinically significant and/or rapidly accumulating ascites, peri-cardial and/or pleural effusions
• Severe or unstable cardiac disease
• Current, known CNS malignancy
• Use of anti-platelet or anti-coagulation medication
• Use of the following anti-viral agents: ribavirin, adefovir, cidofovir (within 7 days prior to the first treatment), and PEG-IFN (within 14 days prior to the first treatment).
• Patients with household contacts who meet any of these criteria unless alternate living arrangements can be made during the patient's active dosing period and for 7 days following the last dose of study medication:
• Pregnant or nursing an infant
• Children < 12 months old
• History of exfoliative skin condition that at some stage has required systemic therapy
• Significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication