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Phase I Trial of Intratumoral Injection of Vesicular Stomatitis Virus Expressing Human Interferon Beta in Patients With Sorafenib Refractory/Intolerant Hepatocellular Carcinoma

Phase 1
18 Years
Open (Enrolling)
Adult Primary Hepatocellular Carcinoma, Recurrent Adult Primary Liver Cancer

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Trial Information

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

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

- Pregnant or nursing women

- History of bone marrow or solid organ transplantation

- Patient for whom surgical resection or liver transplantation would be more

- Any condition, which in the opinion of the investigator would render the patient
unsuitable to participate in the study

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

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.

Outcome Time Frame:

Up to 4 weeks

Safety Issue:


Principal Investigator

Mitesh Borad, M.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

August 2012

Completion Date:

Related Keywords:

  • Adult Primary Hepatocellular Carcinoma
  • Recurrent Adult Primary Liver Cancer
  • virotherapy
  • oncolytic virus
  • vesicular stomatitis virus
  • interferon beta
  • tumor necrosis factor
  • protein kinase R
  • signal transducer and activator of transcription
  • natural killer cell
  • heat shock proteins
  • interferon regulatory factor
  • major histocompatibility class antigens
  • TNF-related apoptosis-inducing ligand
  • CD8+ T cell
  • Hepatocellular Carcinoma
  • Carcinoma
  • Liver Neoplasms
  • Stomatitis
  • Vesicular Stomatitis
  • Carcinoma, Hepatocellular



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