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CPT-11: the European clinical development
C Terret1, C Couteau, J P Armand
1Institut Gustave Roussy, Villejuif, France.
The Journal of Infusional Chemotherapy
|July 1, 1996
Summary
CPT-11, a topoisomerase I inhibitor, shows broad antitumor activity. Phase I trials established a recommended dose and schedule for further studies, demonstrating efficacy in various cancers.
Area of Science:
- Oncology
- Pharmacology
Background:
- CPT-11 is a camptothecin derivative with significant antitumor activity.
- It functions as a selective DNA topoisomerase I inhibitor, similar to camptothecin.
Purpose of the Study:
- To determine the optimal dose and administration schedule for CPT-11 in Phase II trials.
- To assess the toxicity and tolerability of CPT-11 across different schedules.
Main Methods:
- Phase I clinical trials involving 235 patients were conducted in Europe.
- Three administration schedules were evaluated: once every 3 weeks, weekly for 3 out of 4 weeks, and daily for 3 consecutive days every 3 weeks.
- Dose-limiting toxicities and maximum tolerated doses (MTD) were identified for each schedule.
Main Results:
- The MTD was 115 mg/m² for the daily schedule and 145 mg/m² for the weekly schedule.
- Diarrhea was the dose-limiting toxicity for the once every 3 weeks schedule, occurring above 350 mg/m².
- The once every 3 weeks schedule demonstrated the highest dose intensity, best tolerability, and convenience, with loperamide allowing escalation to 750 mg/m².
- Preliminary results of a CPT-11 and 5-FU combination trial showed no pharmacokinetic interaction.
Conclusions:
- CPT-11 at 350 mg/m² administered intravenously over 30 minutes once every 3 weeks was recommended for Phase II trials.
- CPT-11 has demonstrated notable efficacy in colorectal cancer, including 5-FU resistant cases, and promising results in pancreatic, cervical, and lung cancers.
- Future research will focus on combining CPT-11 with other agents or radiotherapy.