CPT-11: the European clinical development.
CPT-11 is a camptothecin derivative with a broad spectrum of antitumor activity, both in vitro and in vivo. Like camptothecin, CPT-11 is a selective DNA topoisomerase I inhibitor. Phase I trials were conducted in Europe to determine the dose and schedule for phase II trials. These phase I trials assessed the toxicity of CPT-11 in 235 patients and tested three administration schedules: a single infusion once every 3 weeks; a weekly infusion for 3 out of 4 weeks; and a daily infusion for 3 consecutive days every 3 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 3 weeks, diarrhea became the dose-limiting toxicity at doses above 350 mg/m2. This schedule offered the highest dose intensity and the best tolerability profile, and was the most convenient for outpatient treatment. Finally, using this schedule, concomitant administration of high-dose 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 show no pharmacokinetic interaction between the two drugs, contrary to a previous Japanese study. Based on the results of the three phase I trials, CPT-11 350 mg/m2 as an intravenous infusion over 30 minutes once every 3 weeks was recommended for phase II trials, which started in Europe in 1992. To date, CPT-11 has shown remarkable efficacy in colorectal cancer, even in patients resistant to 5-FU. Interesting results have also been obtained in pancreatic, cervical and lung cancers. Future trials will explore the place of CPT-11 in combination with other cytotoxic agents or radiotherapy.
Terret
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Institut Gustave Roussy, Villejuif, France.
Couteau
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Armand
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JP
D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin