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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
N/A
Open (Enrolling)
Both
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


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

Type of Study:

Interventional

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:

Yes

Principal Investigator

Mitesh Borad, M.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

MC1148

NCT ID:

NCT01628640

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

Name

Location

Mayo ClinicScottsdale, Arizona