A Study of Recombinant Vaccinia Virus to Treat Unresectable Primary Hepatocellular Carcinoma

• Safety and tolerability of JX-594 administered at two dose levels [ Time Frame: Safety evaluation throughout study participation ] [ Designated as safety issue: Yes ]
• Time-to-tumor progression (TTP) [ Time Frame: Throughout study participation ] [ Designated as safety issue: No ]
• Best radiographic response (based on modified RECIST and modified Choi) [ Time Frame: Periodically throughout study participation ] [ Designated as safety issue: No ]
• Progression Free Survival (PFS) [ Time Frame: Ongoing ] [ Designated as safety issue: No ]

• Best overall response for injected tumors [ Time Frame: Initial response assessment at 4 weeks after last dose ]
• Safety and tolerability of JX-594 administered at two dose levels [ Time Frame: Safety evaluation throughout study period ]
• Best overall response for non-injected tumors [ Time Frame: Initial response assessment at 4 weeks after last dose ]

The purpose of this research study is to determine whether JX-594 (Pexa-Vec) has significant anti-tumoral activity and tolerability in primary hepatocellular carcinoma and to determine the dose to be used in further testing.

Hepatocellular carcinoma (HCC) is estimated to be the third most common cause of cancer-related deaths world-wide, and the fifth most common cancer diagnosis. According to the National Cancer Institute (NCI), approximately 17,000 new cases of HCC are diagnosed annually in the U.S. In Canada, the predicted incidence for 2007 is 1,350 new cases. In addition, approximately 10,000 new cases are diagnosed per year in S. Korea, 35,000 in the E.U. and 45,000 in Japan.

The five-year survival rate is estimated to be <10% for all HCC patients. Given the poor prognosis of these patients there is a desperate need for new therapies.

Surgical resection and liver transplant are the only curative treatment for HCC. Small HCC tumor(s) (less than 3 cm in diameter) can be resected by hepatectomy, the most effective treatment. Surgery was associated with a reported 50-60% five-year survival rate, but unfortunately was possible in only 10-15% of cases. Liver transplant is considered for patients with tumors that are unresectable but that are still limited exclusively to the liver, have no extracapsular or vascular invasion within the liver, and for whom there are no medical contraindications to transplantation. Patients with unresectable HCC that cannot receive liver transplantation, and who do not require systemic therapy, may be administered percutaneous ethanol injection therapy (PEIT), radiofrequency ablation (RFA), transarterial chemoembolization (TACE), and/or radioembolization, depending on the size of the intrahepatic tumors and the underlying liver function.

HCC may be a good target for IT injection with JX-594 because of the relatively high rate of accessible tumors for injection, the positive response seen in a patient with HCC in a recently completed Phase I study of JX-594 intratumoral injection within the liver, excellent tumor responses in multiple preclinical cancer models, and the lack of effective, tolerable therapy for most patients with HCC who cannot receive curative surgery or immediate liver transplantation. Furthermore, it is speculated that JX-594 replication targets the EGFR pathway, and that it's spread within and between tumors is dependent upon the intratumoral vasculature; HCC has highly activated angiogenesis and EGFR pathways in the majority of cases.

• Experimental: 1
  1e8 pfu (plaque forming units) total dose of JX-594 (recombinant vaccinia virus) on each of three (3) treatment days (2 weeks apart)
  Intervention: Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)
• Experimental: 2
  1e9 pfu (plaque-forming units) total dose of JX-594 (recombinant vaccinia virus) on each of three (3) treatment days (2 weeks apart)
  Intervention: Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)

• Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim HY, Chung HC, Kim CW, Burke J, Lencioni R, Hickman T, Moon A, Lee YS, Kim MK, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney C, Bell JC, Rhee BG, Patt R, Hwang TH, Kirn DH. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013 Mar;19(3):329-36. doi: 10.1038/nm.3089. Epub 2013 Feb 10.
• Breitbach CJ, Arulanandam R, De Silva N, Thorne SH, Patt R, Daneshmand M, Moon A, Ilkow C, Burke J, Hwang TH, Heo J, Cho M, Chen H, Angarita FA, Addison C, McCart JA, Bell JC, Kirn DH. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res. 2013 Feb 15;73(4):1265-75. doi: 10.1158/0008-5472.CAN-12-2687. Epub 2013 Feb 7.

Inclusion Criteria

• Histological confirmation or clinical/laboratory diagnosis of primary hepatocellular carcinoma (HCC)
• Cancer is not surgically resectable for cure
• Child Pugh A or B
• Tumor progression during or after at least one prior HCC treatment regimen (Note: If standard HCC therapies are either medically contraindicated or patient has refused those treatments, the patient may be eligible for this study)
• Performance Score: KPS score of ≥ 70
• Anticipated survival of at least 16 weeks
• Total bilirubin ≤ 2.5 x ULN
• AST, ALT < 5.0 x ULN
• WBC > 2,500 cells/mm3 and < 50,000 cells/mm3 (GCSF treatment allowed)
• ANC > 1,250 cells/mm3 (GCSF treatment allowed)
• Hemoglobin ≥ 9 g/dL (RBC transfusion allowed)
• Platelet count ≥ 50,000 plts/mm3
• Acceptable coagulation status: INR ≤ 1.5 x ULN
• Acceptable kidney function: Serum creatinine < 2.0 mg/dL
• If patients are diabetic or have a screening random glucose > 160 mg/dL, a fasting glucose must be done and patients must be WNL or Grade 1 in order to be eligible for the study
• For patients who are sexually active: able and willing to abstain from sex during treatment period and for 3 weeks following treatment, and use an acceptable method of birth control for 3 months after last injection with JX-594
• Able/willing to sign an IRB/IEC/REB-approved written consent form
• Able and willing to comply with study procedures and follow-up examinations, including compliance with the "Infection Control Guidelines for Patients" (in written consent form)

Exclusion Criteria:

• Current, known extra-hepatic tumors that, in the investigator's medical opinion, are likely to result in significant morbidity or mortality within the next 16 weeks.
• Pregnant or nursing an infant
• Known infection with HIV
• Clinically significant active infection or uncontrolled medical condition considered high risk for investigational new drug treatment
• Significant immunodeficiency due to underlying illness (e.g. hematological malignancies, congenital immunodeficiencies and/or HIV infection/AIDS) and/or medication (e.g. high-dose systemic corticosteroids)
• History of exfoliative skin condition (e.g. severe eczema, ectopic dermatitis, or similar skin disorder) that at some stage has required systemic therapy
• Clinically significant and/or rapidly accumulating ascites, peri-cardial and/or pleural effusions
• Liver tumors in a location that would potentially result in significant clinical adverse effects if post-treatment tumor swelling were to occur (e.g. tumors impinging on the biliary tract that could affect drainage)
• Severe or unstable cardiac disease
• Current, known CNS malignancy
• Anti-cancer therapy (e.g. RFA, TACE, PEIT, radioembolization, chemotherapy, surgery, or an investigational drug, etc.) within 4 weeks prior to first treatment
• Absolute contraindication to undergoing MRI scanning
• Experienced a severe systemic reaction or side-effect as a result of a previous smallpox vaccination
• Use of anti-platelet or anti-coagulation medication
• Use of the following anti-viral agents: ribavirin, adefovir, cidofovir (within 7 days prior to the first treatment), and PEG-IFN (within 14 days prior to the first treatment).
• Inability or unwillingness to give informed consent or comply with the procedures required in the protocol
• Patients with household contacts who meet any of these criteria unless alternate living arrangements can be made during the patient's active dosing period and for 7 days following the last dose of study medication:
• Pregnant or nursing an infant
• Children < 12 months old
• History of exfoliative skin condition that at some stage has required systemic therapy
• Significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication