We conducted a phase I and pharmacokinetic study to determine the maximum tolerable dose (MTD), toxicities, pharmacokinetic profile, and antitumor activity of Irinotecan (CPT-11) in patients with refractory solid malignancies. Forty-six patients were entered in this phase I study. CPT-11 was administered intravenously over 30 minutes for 3 consecutive days every 3 weeks. Dose levels ranged from 33 mg/m²/day to 115 mg/m²/day on days 1 through 3. The pharmacokinetics of total CPT-11 and its active metabolite SN-38 were assayed by HPLC. The combination of leukopenia and diarrhea was dose-limiting toxicity at 115 mg/m²/day dose level, since 50% of the patients (5/10) experienced either grade 3–4 leukopenia, or diarrhea, or both. Leukopenia appeared to be a cumulative toxicity, with a global increase in its incidence and severity upon repeated administration of CPT-11. Other toxicities included nausea, vomiting, fatigue and alopecia. CPT-11 and active metabolite SN-38 inetics were determined in 21 patients (29 courses). Both CPT-11 and SN-38 pharmacokinetics presented a high interpatient variability. CPT-11 mean maximum plasma concentrations reached 2034 ng/ml at the MTD (115 mg/m²). The terminal-phase half-life was 8.3 h and the mean residence time 10.2 h. The mean volume of distribution at steady state was 141 l/m²/h. CPT-11 rebound concentrations were observed in many courses at about 0.5 to 1 hour following the end of the i.v. infusion, which is suggestive of enterohepatic recycling. Total body clearance did not vary with increased dosage (mean=14.3 l/h/m²), indicating linear pharmacokinetics within the dose range administered in this trial. The total area under the plasma concentration versus time curve (AUC) increased proportionally to the CPT-11 dose. Mean metabolite SN-38 peak levels reached 41 ng/ml at the MTD. A significant correlation was observed between CPT-11 area under the curve (AUC) and its corresponding metabolite SN-38 AUC (r=0.52, p < 0.05). S-38 rebound concentrations were observed in many courses at about 0.5 to 1 hour following the end of the i.v. infusion, which is suggestive of enterohepatic recycling. Mean 24-h urinary excretion of CPT-11 accounted for 10% of the administered dose by the third day, whereas SN-38 urinary excretion accounted for 0.18% of the CPT-11 dose. In this phase I trial, the hemato-logical toxicity correlated with neither CPT-11 nor SN-38 AUC. Diarrhea grade correlated significantly with CPT-11 AUC. Two partial (breast adenocarcinoma and carcinoma of unknown primary) and 2 minor (hepatocarcinoma and pancreatic adenocarcinoma) responses were observed. The MTD for CPT-11 administered in a 3 consecutive-days-every-3 weeks schedule in this patient population is 115 mg/m²/day. The recommended dose for phase II studies is 100 mg/m²/day.

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