Viral Therapy in Treating Patient With Refractory Liver Cancer or Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of recombinant vesicular stomatitis
virus-expressing interferon-beta (VSV-IFN-beta) in patients with hepatocellular carcinoma
(HCC) refractory or intolerant to sorafenib therapy and patients with advanced solid tumors
with liver predominant locally advanced/metastatic treatment refractory disease. (Arm A) II.
To determine the maximum tolerated dose (MTD) of VSV-IFN-beta in patients with advanced solid
tumors with subcutaneous/cutaneous lesions. (Arm B)

SECONDARY OBJECTIVES:

I. To estimate the tumor response rate, injected lesion (TNi) and distant lesion (TNd)
necrosis rate (with TNi and TNd response defined as >= 30% increase in necrosis from
baseline) and overall survival. (Arm A)

TERTIARY OBJECTIVES:

I. To determine the pharmacokinetic (PK) profile of VSV-IFN-beta in patients with HCC by or
advanced solid tumors with liver predominant disease or subcutaneous/cutaneous lesions by
measurement of VSV-IFN-beta in blood by reverse transcriptase polymerase chain reaction
(RT-PCR).

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

III. Assess CD8+ T cell (both general and VSV-hIFN-beta 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-beta, interferon stimulated gene factor 3 [ISGF3 complex constituting
signal transducer and activator of transcription (STAT)1/2 and p48 (ISGF3 gamma)]).

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-beta (hIFN- beta).

VIII. For HCC patients only, assess preliminary relationships between hepatitis C genotype
(in those patients that are hepatitis C positive) and any evidence of anti-tumor efficacy.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 arms.

ARM A: Patients with hepatocellular carcinoma or advanced solid tumor with liver lesions
receive recombinant vesicular stomatitis virus expressing interferon beta intratumorally in a
single tumor location on day 1.

ARM B: Patients with advanced solid tumor with subcutaneous/cutaneous lesions receive
recombinant vesicular stomatitis virus expressing interferon beta intratumorally in up to 5
lesions on day 1.

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

Inclusion Criteria:

- ARM A: Histologically or cytologically confirmed hepatocellular carcinoma that is
refractory (by Response Evaluation Criteria in Solid Tumors [RECIST] or modified
[m]RECIST criteria or with unequivocal clinical progression of disease) to or
intolerant (defined as inability to administer further sorafenib due to drug related
toxicities) of sorafenib based therapy or advanced solid tumor with liver predominant
disease burden that has progressed on or is intolerant to standard

- ARM A: Absolute neutrophil count (ANC) >= 1000/mm^3

- ARM A: Platelet count >= 80,000/mm^3

- ARM A: Hemoglobin >= 10 g/dl

- ARM A: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5 x ULN

- ARM A: Creatinine =< 1.5 x ULN

- ARM A: Total bilirubin =< 1.5 x ULN

- ARM A: International normalized ratio (INR) =< 1.5 x ULN

- ARM A: Activated partial thromboplastin time (aPTT) =< 1.5 x ULN

- ARM A: Ability to provide informed written consent

- ARM A: Willingness to return to Mayo Clinic in Arizona for follow-up

- ARM A: Life expectancy >= 12 weeks

- ARM A: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- ARM A: Willingness to provide all biological specimens as required by the protocol

- ARM A: Negative serum pregnancy test =< 7 days prior to registration for women of
childbearing potential only

- ARM A: Child Pugh Score A or B7 (patients with ascites must have paracentesis
performed within scope of standard of care, to be able to successfully perform
intratumoral injection procedure)

- ARM A: The patient and their partner agree to use a barrier method of contraception
during the study and 4 months following end of active treatment

- ARM A: Disease burden in liver not affecting more than 25% of liver

- ARM A: Predominant intrahepatic burden (> 75%) of disease (i.e. patients with
widespread extrahepatic disease to organs other than the liver will not be included)

- ARM B: Histologically or cytologically confirmed solid tumor with
subcutaneous/cutaneous lesions that is refractory (RECIST or with unequivocal clinical
progression of disease) to or intolerant to standard therapy

- ARM B: Absolute neutrophil count (ANC) >= 1000/mm^3

- ARM B: Platelet count >= 100,000/mm^3

- ARM B: Hemoglobin >= 10 g/dl

- ARM B: AST/ALT =< 2.5 x ULN

- ARM B: Creatinine =< 1.5 x ULN

- ARM B: Total bilirubin =< 1.5 x ULN

- ARM B: INR =< 1.5 x ULN

- ARM B: aPTT =< 1.5 x ULN

- ARM B: Ability to provide informed written consent

- ARM B: Willingness to return to Mayo Clinic in Arizona for follow-up

- ARM B: Life expectancy >= 12 weeks

- ARM B: ECOG performance status (PS) 0 or 1

- ARM B: Willingness to provide all biological specimens as required by the protocol

- ARM B: Negative serum pregnancy test =< 7 days prior to registration for women of
childbearing potential only

- ARM B: Child Pugh Score A

- ARM B: The patient and their partner agree to use a barrier method of contraception
during the study and 4 months following end of active treatment

- ARM B: Disease burden in liver not affecting more than 25% of liver

Exclusion Criteria:

- ARM A: Uncontrolled infection

- ARM A: Systemic anti-cancer therapy =< 4 weeks prior to registration

- ARM A: Known human immunodeficiency virus (HIV) infection

- ARM A: Other concurrent chemotherapy, immunotherapy, radiotherapy, or investigational
therapy

- ARM A: Pregnant or nursing women

- ARM A: History of bone marrow or solid organ transplantation

- ARM A: Patient for whom surgical resection or liver transplantation would be more
appropriate

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

- ARM A: Any corticosteroid use =< 28 days prior to registration

- ARM A: Any radioembolization or transarterial chemoembolization (TACE) =< 84 days
prior to registration

- ARM B: Uncontrolled infection

- ARM B: Systemic anti-cancer therapy =< 4 weeks prior to registration

- ARM B: Known HIV infection

- ARM B: Other concurrent chemotherapy, immunotherapy, radiotherapy, or investigational
therapy

- ARM B: Pregnant or nursing women

- ARM B: History of bone marrow or solid organ transplantation

- ARM B: Patient for whom surgical resection or liver transplantation would be more
appropriate

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

- ARM B: Any corticosteroid use =< 28 days prior to registration

- ARM B: Any radioembolization or TACE =< 84 days prior to registration