The primary objective of this protocol is to estimate the maximum tolerated dose of irinotecan administered in children with solid tumors whose cancer is refractory to standard therapy. Additionally, investigators will evaluate acute and chronic dose limiting toxicities and describe cumulative toxicity in patients treated with multiple doses. The optimal schedule for irinotecan is not yet known. Antitumor activity has been observed on all schedules of administration that have been studied to date. Preclinical data suggests that a protracted, intermittent dosing schedule is superior to a single bolus dose or a continuous infusion. The most protracted schedule studied in adults to date is a daily x 3 q 3 week schedule (MTD - 90mg/m2/day) and a 120 hr. infusion q 3 week schedule (MTD - 30 mg/m2/day). Therefore, in this trial the starting dose and schedule has be 30 mg/m2/day x 5 days repeated every 21 days. Irinotecan will be administered as a 60 minute intravenous infusion, daily for 5 consecutive days. Courses will be repeated every 21 days. The starting dose will be 30 mg/m2/dose (qd x 5 days). Subsequent dose escalations will be in increments of 30%. Only the first course of therapy will be used to determine the DLT and the MTD. Three evaluable patients will be entered on each dose level. If the patient has clearly progressive disease after 3 weeks of therapy, he/she may be removed from study. If there is response or stable disease (no response) patients should receive a minimum of 2 repeat courses of therapy. The study is currently enrolling patients and therefore no results or conclusions are available at this time. Irinotecan is a unique topoisomerase I inhibitor that has demonstrated significant preclinical as well as clinical antitumor activity. A high degree of activity including cures have been observed in a broad spectrum of murine tumors. Significant antitumor activity has also been reported in xenografts derived from pediatric tumors such as neuroblastoma and rhabdomyosarcoma as well as in rhabdomyosarcoma xenografts selected in vivo for resistance to vincristine, melphalan and topotecan. Significant response rates have been achieved in a variety of solid tumors in adults in Phase I and Phase II studies. Irinotecan appears to be one of the most active topoisomerase I inhibitors that is currently being evaluated and therefore deserves further evaluation in the pediatric population. Depending upon the results of this study, either further Phase I testing will be attempted, or a Phase II trial will be initiated.
Showing the most recent 10 out of 128 publications
