Abstract
A Phase I study was performed to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic profile of irinotecan (CPT-11) and its active metabolites when given on a once-every-3-week schedule. Thirty-four patients with advanced refractory solid malignancies were treated with CPT-11 (240–340 mg/m2) administered as a 90-min i.v. infusion every 3 weeks. Patients were divided into two groups: those with and those without prior abdominal/pelvic (AP) radiotherapy. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and hematological toxicity (leukopenia and neutropenia) were dose-limiting side effects. Other common toxicities included anorexia, asthenia, and acute cholinergic symptoms (abdominal cramps, diaphoresis, and lacrimation). For patients with no prior AP radiation therapy, the MTD was determined to be 320 mg/m2, whereas those with prior AP radiation therapy had a MTD of 290 mg/m2. Dose-proportional increases in the mean area under the concentration-time curves for CPT-11, SN-38, and SN-38G were not observed over the narrow dose range studied. Mean values of terminal phase half-life, clearance, terminal phase volume of distribution, and steady-state volume of distribution for CPT-11 were 12.4 ± 1.8 h, 13.0 ± 3.8 liters/h/m2, 234 ± 83 liters/m2, and 123 ± 38 liters/m2, respectively. The pharmacodynamic analyses indicated the strongest correlation to be between SN-38 area under the concentration-time curves and neutropenia (ρ = 0.60; P = 0.001). A total of five responses (one complete response and four partial responses) were observed in the cohort of 32 patients with previously treated metastatic colorectal carcinoma. In conclusion, gastrointestinal toxicity and hematological toxicity were the dose-limiting toxicities of CPT-11 when administered as a 90-min infusion every 3 weeks. In this trial, the recommended Phase II starting dose for patients with no prior AP radiation therapy was found to be 320 mg/m2; for patients with prior AP radiation, the recommended Phase II starting dose was 290 mg/m2. This once-every-3-week schedule has been incorporated into a Phase I trial of CPT-11 combined with 5-fluorouracil and leucovorin.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported by Pharmacia & Upjohn Company and NIH Grant MO1-RR00585
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↵2 To whom requests for reprints should be addressed, at Division of Medical Oncology, Mayo Clinic Cancer Center, 200 First Street SW, Rochester, MN 55905. Phone: (507) 284-4718; Fax: (507) 284-1803.
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↵3 The abbreviations used are: topo-I, topoisomerase I; CPT-11, irinotecan; MTD, maximum tolerated dose; DLT, dose-limiting toxicity; AP, abdominal/pelvic; 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; IS, internal standard; AUC, area under the concentration-time curves; Cmax, peak plasma concentrations; Tmax, the time at which Cmax occurred; CL, clearance; Vz, terminal phase volume of distribution; Vss, steady-state volume of distribution; t1/2Z, terminal phase half-life.
- Accepted March 6, 2000.
- Received August 6, 1999.
- Revision received March 1, 2000.
Volume 6, Issue 6
