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.
Inclusion Criteria:
- Histologically or cytologically confirmed hepatocellular carcinoma that is refractory to or intolerant of sorafenib based therapy
- Absolute neutrophil count (ANC) >= 1000/mm^3
- Platelet count >= 80,000/mm^3
- Hemoglobin >= 10 g/dl
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5 times upper limit of normal
- Creatinine within institutional limits of normal
- Total bilirubin =< 3 x upper limit of normal (ULN)
- International normalized ratio (INR) =< 1.4 x ULN
- Activated partial thromboplastin time (aPTT) within institutional limits of normal
- Ability to provide informed written consent
- Willingness to return to Mayo Clinic in Arizona for follow-up
- Life expectancy >= 12 weeks
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- Willingness to provide all biological specimens as required by the protocol
- Negative serum pregnancy test =< 7 days prior to registration for women of childbearing potential only
- Child Pugh Score A or B7
- The patient and their partner agree to use a barrier method of contraception during the study and 4 months following end of active treatment
Exclusion Criteria:
- Uncontrolled infection
- Systemic anti-cancer therapy =< 4 weeks prior to registration
- Known human immunodeficiency virus (HIV) infection
- Other concurrent chemotherapy, immunotherapy, radiotherapy, or investigational therapy
- Pregnant or nursing women
- History of bone marrow or solid organ transplantation
- Patient for whom surgical resection or liver transplantation would be more appropriate
- Any condition, which in the opinion of the investigator would render the patient unsuitable to participate in the study
Last updated: 10/04/2012
NCT ID: NCT01628640
IRB Number:11-007114
Find Mayo Clinic on