Irinotecan, which targets the DNA metabolizing enzyme topoisomerase I, recently received an expedited indication for use in patients with metastatic colon cancers. This indication, the first for a new cytotoxic agent for use in colon cancer in over forty years, is based on phase II clinical trials which demonstrated an 18% to 50% response rate. These clinical trials did not investigate the molecular characteristics of responders versus nonresponders. As a consequence, the future use of Irinotecan will be based on empiric strategies rather than mechanistic based applications unless molecular and pharmacologic parameters of response are examined in future trials. This application requests support for such a mechanism based phase II clinical trial which is designed to interrogate the molecular and pharmacologic characteristics of metastatic colon cancers that respond to Irinotecan. The applicant has found that the topoisomerase I found in clinical colon cancers varies widely in sensitivity to Irinotecan. Proliferative rate and mutation of p53 are additional variables that may alter clinical colon cancer response to Irinotecan. It is also known that there is significant individual subject variability in the pharmacokinetics of Irinotecan and its active metabolite SN38. These factors are likely to be important as determinants of those patients who respond to Irinotecan. A highly interactive team will address these issues by analyzing the molecular characteristics of sequential tumor biopsies obtained from patients receiving Irinotecan for metastatic colon cancer and correlate these characteristics with clinical response and individual pharmacokinetics parameters.
