CWRU 1296: Biochemical and Pharmacokinetic Predictors of Colon Cancer Response to a Topoisomerase I Directed Treatment With Irinotecan

OBJECTIVES: I. Confirm the greater than 20% response rate to irinotecan in patients with metastatic or recurrent colorectal cancer who have not receive prior chemotherapy for their advanced disease. II. Characterize pharmacokinetic parameters of irinotecan and its metabolite SN-38 and their relationship to response and toxic effect. III. Characterize tumor samples for topoisomerase I activity, proliferative fraction (ki67 expression), and p53 expression and determine whether clinical response is related to these tumor characteristics in patient population. IV. Determine the in vitro inhibition of topoisomerase I activity by irinotecan, SN-38, and other camptothecin analogs and evaluate whether the degree of in vitro sensitivity to irinotecan and/or SN-38 is associated with clinical response in these patients. VII. Determine the frequency of somatic mutations following irinotecan and correlate this with pharmacologic parameters.

OUTLINE: Patients receive irinotecan IV at a starting dose weekly for 4 weeks followed by 2 weeks of rest. Treatment continues in the absence of disease progression or unacceptable toxicity. Tumor status is reassessed every 12 weeks during study. Patients attaining a complete response may receive additional courses of treatment. Patients are followed until death.

PROJECTED ACCRUAL: A total of 54 patients will be accrued into this study at a rate of 25 patients per year.