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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II-a, Open-Label, Randomized Study of JX-594 (Thymidine Kinase-deleted Vaccinia Virus Plus GM-CSF) Administered by Intratumoral Injection in Patients With Unresectable Primary Hepatocellular Carcinoma

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose<br>1e8 pfu (plaque forming units) total dose of JX-594 (recombinant vaccinia virus) on each of three (3) treatment days (2 weeks apart) | Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)<br>* Patients will be randomized 1:1 to one of two total doses (1e8 or 1e9 pfu)and injected intratumorally in 1-5 intrahepatic tumors on Days 1, 15, and 29.<br>|
| Experimental: High Dose<br>1e9 pfu (plaque-forming units) total dose of JX-594 (recombinant vaccinia virus) on each of three (3) treatment days (2 weeks apart) | Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)<br>* Patients will be randomized 1:1 to one of two total doses (1e8 or 1e9 pfu)and injected intratumorally in 1-5 intrahepatic tumors on Days 1, 15, and 29.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Achieving Disease Control (Non-progressive Disease) at 8 Weeks After Initiation of Treatment | Proportion of subjects achieving disease control at 8 weeks based on a modified Response Evaluation Criteria in Solid Tumors v1.0 (mRECIST). Per mRECIST for target lesions as assessed by dynamic contrast enhanced dynamic MRI: Complete Response (CR), Disappearance of all tumor(s); Partial Response (PR), >=30% decrease in the sum of longest diameter (LD) of tumor(s) taking as reference the baseline sum; Stable Disease (SD), any cases that do not qualify for PR or progressive disease (PD); PD, any increase of >= 20% in the sum of longest diameter (LD) of tumor(s) taking as reference the baseline sum. Disease Control (DC) = CR or PR or SD. For mRECIST criteria, new tumor(s) that developed within the liver were measured (a new tumor was defined as a malignant tumor not present at baseline, was ≥ 1 cm in LD had typical hypervascular features of HCC). Their maximum diameter(s) were included in the sum of the maximum diameter; new tumors were not considered evidence for progression. | Initial progression status and response assessment at 8 weeks from first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of JX-594 Administered at Two Dose Levels | Treatment-related serious adverse events in patients treated at two dose levels | Safety and tolerability were evaluated throughout the 8 week period of study participation | 
| Number of Subjects Achieving Disease Control as Determined Using Intrahepatic Modified RECIST Criteria | Number of subjects achieving disease control (non-progressive disease) at 8 weeks after treatment was initiated based on modified Response Evaluation Criteria in Solid Tumors for Hepatocellular Carcinoma (mRECIST for HCC). mRECIST for HCC adopted the concept of viable tumor as tumor tissue showing uptake in arterial phase of contrast enhanced radiologic imaging techniques. (see Lencioni and Llovet, Semin. Liver Dis. 2010; 30:52-60). Per mRECIST for HCC, for target lesions as assessed by contrast enhanced dynamic MRI: Complete Response (CR), Disappearance of any intratumoral arterial enhancement in all target (viable) lesions; Partial Response (PR), >=30% decrease in the sum of diameters of viable target lesions; Stable Disease (SD), any cases that do not qualify for PR or progressive disease (PD); PD, any increase of >= 20% in viable target lesions. Disease Control (DC) = CR or PR or SD. | At week 8 | 
| Median Overall Survival | Overall survival after treatment in days | To 760 days post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCC, Jennerex, unresectable primary hepatocellular carcinoma, hepatocellular carcinoma, liver cancer, Phase 2, oncolytic virus, Pexa-Vec