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Phase I and Pharmacokinetic Study of the Camptothecin Derivative Irinotecan, Administered on a Weekly Schedule in Cancer Patients¹

Medical Oncology Department, Saint-Louis Hospital, Paris [J. M. E., S. C., I. M., M. E. M.]; Laboratory of Clinical Pharmacology (URA 147 CNRS and U 140 INSERM), Institute Gustave-Roussy, Villejuif [G. G. C., A. G.]; Centre Claudius-Régaud, Toulouse [M. d. F., R. B.]; and, Laboratoire Roger-Bellon, Neuilly-sur-Seine [A. M. B.], France

Irinotecan (CPT-11) is a novel water-soluble, semisynthetic derivative of camptothecin, with inhibitory effects on mammalian DNA topoisomerase I, high cytotoxic activity in vitro and anticancer activity in animal models. Fifty-nine patients, with cancer refractory to conventional therapy, were entered in this phase I study, using a weekly schedule administration. A total of 304 weekly doses were administered at dose levels ranging from 50 to 145 mg/m² (30–90 min i.v. infusion). Leukoneutropenia and diarrhea were the dose-limiting toxicities and appeared to be dose related, reversible and noncumulative. However, interpatient variability of toxic effects was substantial. Prolongation of the infusion time from 30 min to 90 min appeared to decrease the diarrhea. Other toxicities included moderate emesis, asthenia, alopecia, abdominal pain, and anemia. CPT-11 plasma disposition was bi- or triphasic with a terminal half-life of 9.3 h. CPT-11 area under the plasma concentration versus time curves increased linearly with dose (r = 0.47, P < 0.01). The active metabolite area under the plasma concentration versus time curve correlated significantly with that of CPT-11, but not with that of CPT-11 dose. Both CPT-11 and 7-ethyl-10-hydroxycamptothecin areas under the plasma concentration versus time curve correlated significantly with leukoneutropenia and diarrhea. One partial and 4 minor responses were observed at dose levels of 130 and 145 mg/m². Using this weekly schedule, recommended doses for phase II studies are 100 mg/m² in high risk patients and 115 mg/m² in others.

¹ This study was supported by the Laboratoire Roger-Bellon, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), and the Association pour la Recherche sur le Cancer.

² To whom requests for reprints should be addressed at: Medical Oncology Department, Saint-Louis Hospital, 1 Avenue Claude Vellefaux, F75010 Paris, France.

³ Groupe Français d'Étude Clinique Précoce du CPT-11.

Received 12/28/93. Accepted 6/ 8/94.

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