Phase 1b Dose Escalation Study of Intravenous JX-594 in Metastatic, Refractory Colorectal Carcinoma

This is a Phase Ib, open-label, dose-escalation study designed to evaluate the safety and tolerability of Pexa-Vec (JX-594), a vaccinia GM-CSF/thymidine kinase-deactivated virus, administered intravenously in patients with advanced/metastatic colorectal carcinoma (CRC) that is refractory to standard therapy. Vaccinia virus, from which Pexa-Vec is derived, shows a natural selectivity toward cancer relative to normal tissues after intravenous (IV) administration.

The study utilizes a sequential dose-escalating design to determine the maximum tolerated dose (MTD) and/or maximum feasible dose (MFD). Patients will receive 4 biweekly treatments of Pexa-Vec administered by IV infusion over 60 minutes on Days 1, 15, 29, and 43. Patients will be sequentially enrolled into one of three dose cohorts:

• Cohort 1: 1 × 10^6 pfu/kg
• Cohort 2: 1 × 10^7 pfu/kg
• Cohort 3: 3 × 10^7 pfu/kg Three patients will be treated at each dose level unless a dose-limiting toxicity (DLT) is observed, at which point the cohort may be expanded. All patients will receive hydration and will be observed in the clinic and/or hospital for a minimum of 24 hours after each infusion.

In addition to safety endpoints, secondary objectives include the evaluation of Pexa-Vec pharmacokinetics (PK), pharmacodynamics, immune response, and preliminary anti-tumoral activity. Tumor response assessments will be conducted using CT or MRI on Days 29 and 57 (±2 days) based on Response Evaluation Criteria in Solid Tumors (RECIST).

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)