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A Phase I and Pharmacokinetic Study of Fixed-Dose Selenomethionine and Irinotecan in Solid Tumors

Authors' Affiliations: Departments of ¹ Medicine, ² Epidemiology, ³ Pharmacology, and ⁴ Biostatistics, Roswell Park Cancer Institute; and ⁵ Department of Medicine, University at Buffalo School of Medicine and Biomedical Sciences; ⁶ Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York; ⁷ Sabinsa Pharmaceutical, Inc., Piscataway, New Jersey

Requests for reprints: Marwan Fakih, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3362; Fax: 716-845-8008; E-mail: marwan.fakih{at}roswellpark.org.

Purpose: We conducted a phase I study to determine the maximum tolerated dose (MTD) of irinotecan with fixed, nontoxic high dose of selenomethionine.

Experimental Design: Selenomethionine was given orally as a single daily dose containing 2,200 µg of elemental selenium (Se) starting 1 week before the first dose of irinotecan. Irinotecan was given i.v. once weekly x 4 every 6 weeks (one cycle). The starting dose of irinotecan was 125 mg/m²/wk. Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for selenium and irinotecan and its metabolites.

Results: Three of four evaluable patients at dose level 2 of irinotecan (160 mg/m²/wk) had a dose-limiting diarrhea. None of the six evaluable patients at dose level 1 (125 mg/m²/wk irinotecan) had a dose-limiting toxicity. One patient with history of irinotecan-refractory colon cancer achieved a partial response. The long half-life of selenium resulted in a prolonged accumulation towards steady-state concentrations. No significant changes in the pharmacokinetics of CPT-11, SN-38, or SN-38G were identified; however, the coadministration of selenomethionine significantly reduced the irinotecan biliary index, which has been associated with gastrointestinal toxicity.

Conclusions: Selenomethionine at 2,200 µg/d did not allow the safe escalation of irinotecan beyond the previously defined MTD of 125 mg/m². None of the patients receiving 125 mg/m² of irinotecan had grade >2 diarrhea. Unexpected responses and disease stabilizations were noted in a highly refractory population. Further escalation of selenomethionine is recommended in future trials to achieve defined protective serum concentrations of selenium.

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