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

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

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Colorectal
• Intervention / Treatment: Drug: Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594)

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Samsung Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: single arm; Dose escalation; 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); 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.; Other Names: JX-594

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jennerex Biotherapeutics
• Collaborators: Samsung Medical Center

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: June 22, 2011
• First Submitted That Met QC Criteria: June 22, 2011
• First Posted (Estimate): June 27, 2011

Study Record Updates

• Last Update Posted (Estimate): January 8, 2016
• Last Update Submitted That Met QC Criteria: January 6, 2016
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Colorectal cancer; Rectal Cancer; Colon Cancer; Vaccinia; Vaccinia Virus; JX-594; Jennerex; Colorectal Carcinoma; Pexa-Vec
• Additional Relevant MeSH Terms: Digestive System Diseases; Virus Diseases; Infections; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; DNA Virus Infections; Intestinal Neoplasms; Rectal Diseases; Poxviridae Infections; Carcinoma; Colorectal Neoplasms; Vaccinia; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Sargramostim; Molgramostim
• Other Study ID Numbers: JX594-IV-CRC014