Phase I study of an oral formulation of irinotecan administered daily for 14�days every 3�weeks in patients with advanced solid tumours

Abstract

A phase I study was conducted with oral irinotecan given daily for 14 days every 3 weeks in 45 patients with solid tumours to establish the maximum tolerated dose (MTD), toxicity, preliminary antitumour response and pharmacokinetics. Irinotecan was administered orally as a powder-filled capsule at doses ranging from 7.5 to 40 mg/m2 per day. Tumours were predominantly colorectal (30) together with 10 other gastrointestinal, 2 breast, 2 small cell lung and 1 ovarian. All but three patients had received prior chemotherapy. The median number of administered cycles was 3 (range 1-19). Gastrointestinal toxicities (grade 3 nausea, grade 3/4 vomiting and diarrhoea) and one incidence of grade 3 asthenia were dose limiting. There were no grade 3/4 haematological toxicities. The MTD was 30 mg/m2 per day. There were two documented partial responses, one in a patient with cancer of the small intestine and the other in a patient with colon cancer. Stable disease was seen in 16 patients (35.5%). Peak concentrations of irinotecan and metabolite SN-38 were reached within 2.0-2.4 h. The metabolic ratio of SN-38 AUC to irinotecan AUC was 0.17+/-0.10 (mean+/-SD). The dose recommended for phase II studies is 30 mg/m2 per day administered daily for 14 days every 3 weeks.

Dose-Finding Phase I Clinical and Pharmacokinetic Study of Orally Administered Irinotecan in Patients with Advanced Solid Tumors

“…In our previous study, the advised future dose was 30 mg/m 2 /d for 14 days every 3 weeks (1). This was also found earlier by Sharma et al (1,35,36). In both studies, the most commonly observed DLT was diarrhea.…”

“…The appropriate daily dose of irinotecan capsules was based on the actual calculated body surface area. The starting dose as a single agent was based on a previous study (1), in which powder-filled capsules were used. In part II of the study, irinotecan was administered as in part I, orally, once daily with capecitabine, orally twice daily at the end of a meal (breakfast and dinner) from days 1 to 14 every 3 weeks.…”

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

“…Recently, an oral formulation of irinotecan has been developed and has entered phase I clinical trials (Schoemaker et al, 2002). Since chronic infusions are cumbersome and expensive, an oral formulation provides an excellent method to administer irinotecan over a prolonged period at low doses.…”

Novel Therapeutic Developments Other Than EGFR and VEGF Inhibition in Colorectal Cancer

“…infusion and is converted to its active metabolite SN-38 by carboxylesterase [24]. Oral irinotecan has unpredictable bioavailability, but some form of oral agent would have practical advantages, especially if used with an oral fluoropyrimidine [24][25][26][27][28]. No interaction between oral irinotecan and capecitabine was observed in a pharmacokinetic study [28].…”