Phase I and pharmacokinetic trial of weekly CPT-11

• Published in: Journal of clinical oncology Vol. 11; no. 11; p. 2194
• Main Authors: Rothenberg, M L, Kuhn, J G, Burris, 3rd, H A, Nelson, J, Eckardt, J R, Tristan-Morales, M, Hilsenbeck, S G, Weiss, G R, Smith, L S, Rodriguez, G I
• Format: Journal Article
• Language: English
• Published: United States 01.11.1993
• Subjects: Adult; Aged; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - pharmacokinetics; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Chromatography, High Pressure Liquid; Drug Administration Schedule; Female; Humans; Least-Squares Analysis; Male; Middle Aged; Neoplasms - drug therapy
• ISSN: 0732-183X
• DOI: 10.1200/jco.1993.11.11.2194

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. 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. 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 (Cpmax) and between drug dose and area under the concentration curve (AUC) for CPT-11, but not for SN-38. 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.