Viral Therapy in Treating Patient With Liver Cancer

• MTD, defined as the highest dose at which no more than 1/6 patients experiences dose limiting toxicities (DLT), graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: Yes ]
  DLT defined as an adverse event during the first 4 weeks following injection. A modified "3+3" Fibonacci dose escalation scheme will be used Examined in an exploratory and hypothesis-generating fashion.
  
  
• Incidence of adverse events, graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  All eligible patients that have initiated treatment will be considered evaluable for assessing adverse event rate(s). The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed by dose level to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Examined in an exploratory and hypothesis-generating fashion.
  
  
• Best tumor response, defined as the best objective status recorded among patients with measurable disease at baseline using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: From the start of the treatment until disease progression, assessed up to 3 years ] [ Designated as safety issue: No ]
  Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by dose level). Examined in an exploratory and hypothesis-generating fashion.
  
  
• Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
  The distribution of survival time will be estimated using the method of Kaplan-Meier (overall and by dose level). Examined in an exploratory and hypothesis-generating fashion.
  
  

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of vesicular stomatitis virus (VSV)-interferon beta (IFN-β) (recombinant vesicular stomatitis virus expressing interferon beta) in patients with hepatocellular carcinoma (HCC) refractory or intolerant to sorafenib therapy.

SECONDARY OBJECTIVES:

I. To estimate the tumor response rate and overall survival.

TERTIARY OBJECTIVES:

I. To determine the pharmacokinetic (PK) profile of VSV-IFN-β in patients with HCC by measurement of VSV-IFN-β in blood by reverse transcriptase polymerase chain reaction (RT-PCR).

II. To characterize the pharmacodynamics (PD) of VSV-IFN-β by way of measuring serum interferon-β and also VSV-RT-PCR of VSV-IFN-β listed above.

III. Assess CD8+ T cell (both general and VSV-hIFN-β specific) and natural killer (NK) cell responses.

IV. Assess status of human interferon beta pathway pre/post therapy in tumor/normal liver tissue (status of IFN-β, interferon stimulated gene factor 3 [ISGF3 complex constituting signal transducer and activator of transcription (STAT)1/2 and p48 (ISGF3 γ)]).

V. Assess phosphorylation of STAT1/2 post-therapy. VI. Evaluate transcription of interferon mediated genes (protein kinase R, the death receptor-tumor necrosis factor [TNF]-related apoptosis-inducing ligand [TRAIL], 2'-5' oligoadenylate/ribonucleic acid [RNA]se L proteins, heat shock proteins [Hsp 60/70/90], major histocompatibility class antigens and interferon regulatory factor [IRF]-7).

VII. Assess presence of VSV in tumor/normal liver subsequent to administration of VSV-human IFN-β (hIFN- β).

OUTLINE: This is a dose-escalation study.

Patients receive recombinant vesicular stomatitis virus expressing interferon beta intratumorally on day 1.

After completion of study treatment, patients are followed up every 4 weeks for up to 3 years.