Safety Study of Recombinant Vaccinia Virus to Treat Refractory Solid Tumors

Study Overview
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Brief Summary
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This is a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors refractory to standard therapy; tumors may include malignant melanoma, non-small cell lung cancer, renal cell carcinoma, and squamous cell carcinoma of the head and neck. These tumor types were selected because evidence of biological activity was observed in these tumor types in a Phase I study of JX-594 (Pexa-Vec) administered by intratumoral injection in patients with metastatic disease to the liver. Patients will receive treatment at one of five dose levels in a sequential dose-escalating design.

Official Title
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A Phase I Dose Escalation Study of JX-594 (Thymidine Kinase-deleted Vaccinia Virus Plus GM-CSF) Administered by Intravenous Infusion in Patients With Refractory Solid Tumors

Conditions
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Melanoma, Lung Cancer, Renal Cell Carcinoma, Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed, advanced/metastatic solid tumor refractory to standard therapy or the patient has refused or does not tolerate the standard therapy; tumors may include malignant melanoma, non-small cell lung cancer, renal cell carcinoma, and squamous cell carcinoma of the head and neck At least one measurable tumor mass by CT/MRI (i.e. lesion that can accurately be measured in at least one dimension with longest diameter > 1 cm) At least one tumor mass amenable to biopsy and/or FNA Expected survival for approximately 16 weeks or longer Karnofsky Performance Score (KPS) ≥ 70 Age ≥18 years WBC ≥ 3,500 cells/mm3 and ≤ 50,000 cells/mm3 ANC ≥ 1,500 cells/mm3 Hemoglobin ≥ 10 g/dL Platelet count ≥ 100,000 plts/mm3 Total bilirubin ≤ 1.5 x ULN AST, ALT ≤ 2.5 x ULN Serum chemistries within normal limits (WNL) or Grade 1 - 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. Acceptable coagulation status: INR ≤ (ULN + 10%) CD4 count ≥ 500/mm3 Exclusion Criteria: Significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication (e.g. systemic corticosteroids) Known myeloproliferative disorders requiring systemic therapy History of exfoliative skin condition (e.g. eczema or ectopic dermatitis) requiring systemic therapy Tumor(s) invading a major vascular structure (e.g. carotid artery) Tumor(s) in location that would potentially result in significant clinical adverse effects if post-treatment tumor swelling were to occur (e.g. tumors impinging on the upper airway or affecting biliary tract drainage, etc.) Clinically significant and/or rapidly accumulating ascites, peri-cardial and/or pleural effusions Severe or unstable cardiac disease Current, known CNS malignancy (history of completely resected or irradiated brain metastases allowed) Received anti-cancer therapy within 4 weeks prior to first treatment (6 weeks in case of mitomycin C or nitrosoureas) Use of anti-viral, anti-platelet, or anti-coagulation medication [Patients who discontinue such medications within 7 days prior to first treatment may be eligible for this study.] Pulse oximetry O2 saturation <90% at rest Experienced a severe systemic reaction or side-effect as a result of a previous smallpox vaccination Household contact exclusions: Women who are pregnant or nursing an infant Children < 5 years old History of exfoliative skin condition (e.g. eczema) that at some stage has required systemic therapy Significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication (e.g. systemic corticosteroids)

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm, dose escalation<br>dose escalation starting dose 1e5 pfu/kg bw to 3e7 pfu/kg bw; Recombinant Vaccinia GM-CSF (JX-594) | Drug: Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594)<br>* Intravenous Dosage from 1 x 10^5 pfu/kg to 3 x 10^7 pfu/kg Intravenous infusion is administered once over a 60 minute period<br>* Other names: JX-594;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximally-tolerated dose (MTD) and/or maximum-feasible dose (MFD) of JX-594 administered by intravenous (IV) infusion |  | 4 weeks | 
| Safety/Toxicity: Incidence of treatment-related adverse events; treatment-related serious adverse events; treatment-related Grade 3/4 toxicities; and clinically-significant, treatment-related changes from baseline in routine laboratory parameters |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the JX-594 pharmacokinetics and pharmacodynamics over time following IV infusion |  | 4 weeks | 
| Determine the immune response to JX-594 following IV infusion |  | 4 weeks | 
| Determine the delivery of JX-594 to, and concentration within, solid tumors following IV infusion |  | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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phase I, advanced metastatic solid tumors, oncolytic virus, vaccinia virus, melanoma, lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, Pexa-Vec