CPT-11. The European experience

Abstract

CPT-11 is a derivative of camptothecin, which has a broad spectrum of antitumor activity, both in vitro and in vivo. Like camptothecin, CPT-11 is a selective inhibitor of the DNA enzyme topoisomerase I. Phase I trials were conducted in Europe with the aim of determining the recommended CPT-11 dose and schedule for evaluation in phase II trials. The phase I trials assessed the toxicity of CPT-11 in 235 patients and tested three different administration schedules. CPT-11 was administered as a single infusion once every three weeks, as a weekly infusion for three weeks out of every four, and as a daily infusion for three consecutive days every three weeks. The maximum tolerated dose (MTD) was 115 mg/m2 in the daily schedule and 145 mg/m2 in the weekly schedule. When the drug was administered once every three weeks, diarrhea became the dose-limiting toxicity at doses above 350 mg/m2. This schedule allowed the highest dose intensity to be obtained, was the best tolerated, and allowed ambulant treatment. Finally, using this schedule, a combination of CPT-11 with high doses of loperamide allowed the dose of CPT-11 to be increased to 750 mg/m2. An ongoing phase I trial is investigating the combination of CPT-11 and 5-fluorouracil (5-FU) in various solid tumors. Although the MTD has not yet been reached, preliminary results have not demonstrated any pharmacokinetic interaction between the two drugs, contrary to the findings of a previous Japanese study. Based on the results of the three phase I trials, CPT-11 administered at a dose of 350 mg/m2 as an intravenous infusion over 30 minutes once every three weeks has been recommended for assessment in phase II trials. The phase II trials started in Europe at the beginning of 1992. To date, CPT-11 has showed remarkable efficacy in colorectal cancer, even in patients resistant to 5-FU. Interesting results have also been obtained in pancreatic, cervical and lung cancer. Future trials will make it possible to assess whether there is a place for CPT-11 in combination with other cytotoxic agents or radiotherapy.