Phase I and pharmacokinetic trial of weekly CPT-11

Purpose: We conducted a phase I and pharmacokinetic trial of CPT-11 (irinotecan) to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetic profile, and antitumor effects in patients with refractory solid malignancies. Patients and Methods: We treated 32 patients with CPT-11 administered as a 90-minute intravenous infusion every week for 4 consecutive weeks followed by a 2-week rest period. Dose levels ranged from 50 to 180 mg/m²/wk. We determined concentrations of the lactone (active) and total (lactone plus carboxylate) forms of CPT-11 and its metabolite, SN-38, in the plasma and urine of selected patients during and after drug infusion. Results: Grade 4 diarrhea was the dose-limiting toxicity (DLT) at the 180- mg/m²/wk dose level. Other toxicities attributed to CPT-11 included dehydration, nausea, vomiting, and asthenia. Hematologic toxicity was mild in most patients. The terminal plasma half-life for CPT-11 (total) was 7.9 ± 2.8 hours, for CPT-11 (lactone) 6.3 ± 2.2 hours, for SN-38 (total) 13.0 ± 5.8 hours, and for SN-38 (lactone) 11.5 ± 3.8 hours. We observed significant correlations between drug dose and peak plasma concentration (C(P)max) and between drug dose and area under the concentration curve (AUC) for CPT-11, but not for SN-38. Conclusion: The MTD for CPT-11 in this patient population was 150 mg/m²/wk when administered on a weekly-times-four schedule repeated every 6 weeks. At dose levels greater than 150 mg/m²/wk, diarrhea is dose- limiting.