Phase 1b Dose Escalation Study of Intravenous JX-594 in 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.

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)