Safety and Efficacy of Targeted Gene Transfer in Colorectal Cancer Metastatic to Liver

Objectives:

1. To evaluate the safety/toxicity of hepatic arterial administration of a matrix-targeted retroviral vector bearing a dnG1 construct (Mx-dnG1)
2. To evaluate the pharmacodynamics of hepatic arterial infusion of the Mx-dnG1 retroviral vector administered as hepatic arterial infusion.
3. To obtain preliminary data on molecular markers of tumor response
4. To identify an anti-tumor response to hepatic artery administered Mx-dnG1 retroviral vector

Population: Male and female patients, >18 years old, with metastatic colorectal carcinoma

Sample Size: Nine to fifteen patients (3 to 6 patients treated at each of three dose levels).

Dosage Treatment: Hepatic arterial infusion of the Mx-dnG1 retroviral vector once a day on days 1-5.

Three patients will receive the Mx-dnG1 retroviral vector at Dose Level I. If 1 of 3 patients at Dose Level I develops a grade 3 or 4 adverse event (CTC Version 2.0) which appears to be related or possibly related to the Mx-dnG1 retroviral vector, then 3 additional patients will be enrolled at the same dose level. If at least 2 of the first 3, or 3 of 6, patients at Dose Level I develop a grade 3 to 4 adverse event which appears to be related or possibly related to the Mx-dnG1 retroviral vector, accrual into the study will be held until the data are discussed with the Food and Drug Administration (FDA) and a decision is made whether to continue or terminate study enrollment.

If none of the first 3 or no more than 1 of the first 6 patients that have received vector at Dose Level I develop a grade 3 or 4 adverse event which appears to be related or possibly related to the dnG1 retroviral vector, the dose of the vector will be escalated as follows:

Dose LeveL---No. of Patients---Vector Dose---Maximum Volume

• I----------------3------------3 X 10e9 cfu-------500 ml
• II---------------3------------6 X 10e9 cfu-------500 ml
• III--------------3------------1 X 10e10 cfu------500 ml

The intervention plan will be identical to the one described above for Dose Level I. The Maximum Tolerated Dose (MTD) will be defined as one dose level below the level at which dose limiting toxicity is observed.

Primary Endpoint: Clinical toxicity (DLT and MTD) as defined by patient performance status, toxicity assessment score, hematologic, liver and coagulation profile.

Secondary Endpoint: Obtain preliminary data on molecular markers of tumor response. To assess decrease in tumor size as detected by abdominal CT Scan at 3 and 6 weeks after treatment. Evaluate the pharmacodynamics of hepatic arterial infusion of the Mx-dnG1 retroviral vector administered as hepatic arterial infusion.