A Study of Recombinant Vaccinia Virus to Evaluate the Safety and Efficacy of a Transdermal Injection Within the Tumor of Patients With Primary or Metastatic Hepatic Carcinoma

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study is to determine the maximum tolerable dose (MTD) and/or the maximum feasible dose (MFD), as well as to evaluate the safety of JX-594 (Pexa-Vec) injected within hepatic carcinoma tumors.

Detailed Description
-----------------
Patients are treated with JX-594 once every three weeks until progression at the site(s) of injection or until the patient has received a maximum of 4 treatments; four additional cycles can be administered to patients with an objective response of the injected tumor(s) (i.e. 8 total treatments possible). Study dose levels are 1e8 pfu, 3e8 pfu, 1e9 pfu and 3e9 pfu per treatment. Standard Phase I dose-escalation guidelines are used, with 2-6 patients enrolled per cohort (3 if no dose-limiting toxicities are reported).

Official Title
-----------------
Phase 1 Clinical Study for Evaluating the Safety and Efficacy of a Transdermal Injection of JX-594 (Thymidine Kinase (-)/GM-CSF(+) Vaccinia Virus) Within the Tumor of Patients With Hepatic Carcinoma

Conditions
-----------------
Neoplasms, Liver

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Patients with hepatic carcinoma (primary or metastatic) clinically or histologically confirmed to have tumors (≤10cm maximum diameter) that are progressing (refractory to standard treatment) despite regular treatment and that can be transdermally accessed by an injection needle in an imaging-guided procedure Tumor progression despite undergoing regular treatment such as surgery, transarterial chemoembolization, chemotherapy, and radiotherapy Performance score: Karnofsky Performance Score (KPS) ≥70 Expected survival of at least 16 weeks For patients who are sexually active, able and willing to use contraceptives for a three month period during and after taking JX-594 WBC > 3,500 cells/mm3 ANC > 1,500 cells/mm3 Hemoglobin > 10g/dL Platelet count > 75,000 plts/mm3 Serum creatinine < 1.5 mg/dL AST, ALT < 2.5 x ULN Total bilirubin ≤ 2.0 mg/dL In patients with primary HCC, Child Pugh A or B Able/willing to sign an IRB/IEC/REB-approved written consent form Able and willing to comply with study procedures and follow-up examinations Exclusion Criteria: 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) Patients with household contacts with significant immunodeficiency History of exfoliative skin condition (e.g. severe eczema, ectopic dermatitis, or similar skin disorder) that at some stage has required systemic therapy Severe or unstable cardiac disease Use of adrenal cortical hormone drug or immunosuppressant within four weeks of study enrollment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>1e8 pfu (plaque forming units)total dose each treatment day | Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)<br>* The total dose is divided between 1-3 tumors located within the liver. Patients are treated with JX-594 once every 3 weeks until progression at the site(s) of injection or until the patient has received a maximum of 4 treatments.<br>|
| Experimental: 2<br>3e8 pfu (plaque forming units) total dose each treatment day | Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)<br>* The total dose is divided between 1-3 tumors located within the liver. Patients are treated with JX-594 once every 3 weeks until progression at the site(s) of injection or until the patient has received a maximum of 4 treatments.<br>|
| Experimental: 3<br>1e9 pfu (plaque forming units) total dose each treatment day | Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)<br>* The total dose is divided between 1-3 tumors located within the liver. Patients are treated with JX-594 once every 3 weeks until progression at the site(s) of injection or until the patient has received a maximum of 4 treatments.<br>|
| Experimental: 4<br>3e9 pfu (plaque forming units) total dose each treatment day | Genetic: JX-594: Recombinant vaccinia virus (TK-deletion plus GM-CSF)<br>* The total dose is divided between 1-3 tumors located within the liver. Patients are treated with JX-594 once every 3 weeks until progression at the site(s) of injection or until the patient has received a maximum of 4 treatments.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerable dose (MTD) and/or the maximum feasible dose (MFD), as well as to evaluate the safety of JX-594 injected within unresectable solid tumor(s) within the liver |  | Safety evaluation throughout study participation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary objectives include determination of JX-594 pharmacokinetics, replication and shedding, immune response, and injection site tumor responses. |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Jennerex, unresectable liver tumors, primary liver cancer, metastatic liver cancer, oncolytic virus, vaccinia virus, Pexa-Vec