Safety and Efficacy of Targeted Gene Transfer in Colorectal Cancer Metastatic to Liver
This is a Phase I safety study of a gene transfer drug for colorectal cancer that has spread to the liver. The main purpose of this study is to determine if it is safe to give this new intervention to persons with cancer, but we will also look for indications that the drug is effective. Although the findings in animals that have cancer are encouraging, this is the first time humans will receive this experimental gene transfer drug. A gene called cyclin G1 has been shown to play a very important part in cancer growth. In animal experiments, a genetically modified virus (or vector)carrying a modified cyclin G1 gene caused the cancerous tumors to grow much slower or even die. In this safety study, the drug will be injected through the liver artery to get it near the cancer that has spread to the liver. The way the gene gets into the cancer cells is by using a targeted vector that concentrates in the area of the cancer to improve the delivery of the killing gene into cancer cells. The vector we are using is a virus that has been changed so that the infectious genes have been removed and instead carries the modified cyclin G1 gene.
Genetic: Mx-dnG1 Retroviral Vector
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Tumor Site Specific Phase I Evaluation of Safety of Hepatic Arterial Infusion of a Matrix-Targeted Retroviral Vector Bearing a Dominant Negative Cyclin G1 Construct as Intervention for Colorectal Carcinoma Metastatic to Liver|
- dose-limiting toxicity and maximum tolerated dose
- objective tumor response by CT scan or MRI
|Study Start Date:||November 2002|
|Estimated Study Completion Date:||October 2003|
- To evaluate the safety/toxicity of hepatic arterial administration of a matrix-targeted retroviral vector bearing a dnG1 construct (Mx-dnG1)
- To evaluate the pharmacodynamics of hepatic arterial infusion of the Mx-dnG1 retroviral vector administered as hepatic arterial infusion.
- To obtain preliminary data on molecular markers of tumor response
- 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.
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