Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors.
BACKGROUND
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.


METHODS
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.


RESULTS
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 pharmacokinetics 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). SN-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 hematological 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.


CONCLUSIONS
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.
Catimel
G
G
Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
Chabot
G G
GG
Guastalla
J P
JP
Dumortier
A
A
Cote
C
C
Engel
C
C
Gouyette
A
A
Mathieu-Boué
A
A
Mahjoubi
M
M
Clavel
M
M
D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016879:Salvage Therapy; D016896:Treatment Outcome
D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin