Safety Study of Recombinant Vaccinia Virus Administered Intravenously in Patients With Metastatic, Refractory Colorectal Carcinoma

Study Overview
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Brief Summary
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The purpose of this pilot safety study is to evaluate the safety and tolerability of JX-594 (Pexa-Vec) administered intravenously every 2 weeks in colorectal carcinoma patients who are refractory to or intolerant of oxaliplatin, irinotecan, and Erbitux treatments.

Official Title
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A Phase 1b Dose Escalation Study of JX-594 (Thymidine Kinase-Inactivated Vaccinia Virus Plus GM-CSF) Administered by Biweekly (Every Two Weeks) Intravenous Infusion in Patients With Metastatic, Refractory Colorectal Carcinoma

Conditions
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Carcinoma, Colorectal

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 colorectal carcinoma Failed both oxaliplatin and irinotecan based regimens for advanced/metastatic disease (if tumor advanced either immediately or within 3 months of the end of treatment) Resistance to Erbitux: patients with Ras mutations, or for whom Erbitux has failed (if tumor advanced either immediately or within 3 months of the end of treatment, or there is no response to Erbitux therapy due to a lack of expression of EGFR (epidermal growth factor)) Karnofsky Performance Score (KPS) ≥ 70 Age ≥18 years Laboratory Safety: WBC ≥ 3,500 cells/mm3 and ≤ 50,000 cells/mm3, ANC ≥ 1,500 cells/mm3, Hemoglobin ≥ 10 g/dL (transfusion allowed), Platelet count ≥ 100,000 plts/mm3,Total bilirubin ≤ 1.5 X ULN, INR ≤ 1.5, AST, ALT ≤ 2.5x ULN (in case of liver metastasis: AST,ALT ≤5.0 x ULN) Serum chemistries within normal limits (WNL) or Grade 1 (excluding alkaline phosphatase) - If patients are diabetic, a fasting glucose must be done and patients must be > 160 mg/dL. Patients who, if they are sexually active, are willing and able to refrain from sexual activity for 3 weeks following JX-594 administration. Patients who are willing and able to use a permitted contraceptive for 3 months after the final administration of JX-594. 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 History of acquiring opportunistic infections. 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 Clinically uncontrolled and/or rapidly accumulating ascites, pericardial and/or pleural effusions History of severe or unstable cardiac disease Current, known CNS malignancy (history of completely resected or irradiated brain metastases by WBRT or stereotactic radiosurgery allowed) Administered 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.] Low dose aspirin (approximately 81 mg) allowed. Pulse oximetry O2 saturation <90% Pulse oximetry O2 saturation <90% at rest Experienced a severe systemic reaction or side-effect as a result of a previous smallpox vaccination Pregnant or nursing Household contact exclusions: Women who are pregnant or nursing an infant Children < 5 years old People with skin disease (e.g. eczema, atopic dermatitis, and related diseases Immunocompromised hosts (severe deficiencies in cell-mediated immunity, including AIDS, organ transplant recipients, hematologic malignancies)

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 |
| --- | --- |
| Other: single arm; Dose escalation<br>Dose escalation 1e6 pfu/kg bw, 1e7 pfu/kg bw, 3e7 pfu/kg bw of Recombinant Vaccinia GM-CSF JX-594 | Drug: Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594)<br>* Intravenous Dose Range: 1x10^6 pfu/kg, 1x10^7 pfu/kg, 3x10^7 pfu/kg Up to 4 intravenous infusions administered over 60 minutes every 2 weeks.<br>* Other names: JX-594;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the maximally-tolerated dose (MTD) and/or maximum-feasible dose (MFD) of JX-594 administered by biweekly intravenous (IV) infusion | Any of the following treatment related adverse events: Grade 4 toxicity, Grade 3 hematologic toxicity for > 5 days, Grade 3 non-hematologic toxicities persisting for > 7 days except for flu-like symptoms that respond to standard therapies. | DLT evaluations through 14 days following last JX-594 treatment | 
| Determine the safety of JX-594 administered by biweekly IV infusion | Adverse events will be collected and assessed to assess safety and tolerability through 28 days after last dose of JX-594 (or until all events considered probably or possibly related to JX-594 have resolved, stabilized, or returned to baseline status). | Safety evaluations through 28 days after last dose of JX-594 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the pharmacokinetics, pharmacodynamics and immune response activity of JX-594 | Change over time in viral genomes, infectious units, GM-CSF concentration, peripheral white blood cell counts, plasma cytokine measurements, and neutralizing antibodies to JX-594 in blood and/or serum. | Blood samples collected at assigned time points from baseline through Week 8 | 
| Determine the anti-tumoral response of JX-594 | Tumor response (Stable, partial, complete, progression) by standard RECIST on CT/MRI. Decrease in tumor blood marker. | Disease control and response assessment at Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vaccinia, Vaccinia Virus, JX-594, Jennerex, Colorectal Carcinoma, Colorectal cancer, Colon Cancer, Rectal Cancer, Pexa-Vec