TY - JOUR
T1 - Phase I and pharmacokinetic trial of weekly CPT-11
AU - Rothenberg, M. L.
AU - Kuhn, J. G.
AU - Burris, H. A.
AU - Nelson, J.
AU - Eckardt, J. R.
AU - Tristan- Morales, M.
AU - Hilsenbeck, S. G.
AU - Weiss, G. R.
AU - Smith, L. S.
AU - Rodriguez, G. I.
AU - Rock, M. K.
AU - Von Hoff, D. D.
PY - 1993/1/1
Y1 - 1993/1/1
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.1993.11.11.2194
DO - 10.1200/JCO.1993.11.11.2194
M3 - Article
C2 - 8229134
AN - SCOPUS:0027140524
VL - 11
SP - 2194
EP - 2204
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 11
ER -