Phase I Trial of Intratumoral Injection of Vesicular Stomatitis Virus Expressing Human Interferon Beta in Patients With Sorafenib Refractory/Intolerant Hepatocellular Carcinoma
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
I. To estimate the tumor response rate and overall survival.
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
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
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
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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
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.
Up to 4 weeks
Mitesh Borad, M.D.
United States: Food and Drug Administration
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