APhase I and Pharmacokinetic Study of Fixed-Dose Selenomethionine and Irinotecan in SolidTumors

We conducted a phase I study to determine the maximum tolerated dose (MTD) of irinotecanwith fixed, nontoxic high dose of selenomethionine.  Selenomethionine was given orally as a single daily dose containing 2,200 Ag of elemental selenium (Se) starting1week before the first dose of irinotecan. Irinotecan was given i.v. once weekly 4 every 6 weeks (one cycle). The starting dose of irinotecan was125 mg/m/wk. Escalation occurred in cohorts of three patients until the MTDwas defined. Pharmacokinetic studies were done for selenium and irinotecan and its metabolites.  Three of four evaluable patients at dose level 2 of irinotecan (160 mg/m/wk) had a dose-limiting diarrhea. None of the six evaluable patients at dose level 1 (125 mg/m/wk irinotecan) had a dose-limiting toxicity. One patient with history of irinotecan-refractory colon cancer achieved a partial response.The longhalf-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, whichhas been associated with gastrointestinal toxicity.  Selenomethionine at 2,200 Ag/d did not allow the safe escalation of irinotecan beyond the previously definedMTDof125 mg/m. None of the patients receiving125 mg/m 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. Selenium is an essential trace element with a worldwide average nutritional intake of 50 to 350 Ag/d. Dietary selenium deficiency has been associated with an increased risk of carcinogenesis and of increased mortality (1, 2). Multiple other epidemiologic studies have suggested that higher selenium blood levels are protective against the development of various solid tumors (3–12). These intriguing results have led to the investigation of selenium as a chemoprevention agent. A landmark study by Clark et al. investigated the use of 200 Ag/d of selenium (as selenized yeast) as a chemoprevention agent for nonmelanoma skin cancer (13). A total of 1,312 patients with history of basal or squamous cell carcinoma of the skin were randomized to receive a selenium supplement or a matching placebo. Although a slight increase in skin cancer occurred in the selenium group, selenium supplementation resulted in significant reduction in the total cancer mortality and total cancer incidence, including lung, colorectal, and prostate cancers (13, 14). Furthermore, a retrospective analysis of baseline selenium levels in patients with non-Hodgkin’s lymphoma showed a positive correlation between serum selenium levels and chemotherapy dose delivery and outcome (response, treatment failure, treatment-related death; ref. 15). In a multivariate analysis, selenium was the most important factor affecting survival with a hazard ratio of 0.76 for every 0.2 Amol/L increase in concentration (15). Given the favorable epidemiologic data and the decreased chemotherapy-related toxicity associated with selenium-replete patients, our group has investigated the utility of high-dose selenium supplementation with chemotherapy in preclinical models. We have shown that the organic selenium compounds selenomethionine and methylselenocysteine selectively modulate the therapeutic efficacy of anticancer drugs in human xenograft models (16). Both selenium compounds reduced the toxicity of irinotecan as evidenced by the ability to administer 2to 3-fold the maximum tolerated dose (MTD) of irinotecan when mice were treated with daily selenomethionine or methylselenocysteine starting 1 week before chemotherapy (16). Although a dose of irinotecan of 200 mg/mouse was associated with 60% lethality, the addition of selenomethionine at 0.2 mg/mouse/d (starting 1 week before chemotherapy) Cancer Therapy:  Departments of Medicine, Epidemiology, Pharmacology, and Biostatistics, Roswell Park Cancer Institute; and Department of Medicine, University at Buffalo School of Medicine and Biomedical Sciences; Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences,Buffalo, NewYork; Sabinsa Pharmaceutical, Inc., Piscataway,NewJersey Received 9/14/05; revised11/8/05; accepted11/30/05.  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 with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Marwan Fakih, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. ; Fax: 716-845-8008; E-mail: marwan.fakih@roswellpark.org.  American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-2004 www.aacrjournals.org Clin Cancer Res 2006;12(4) February15, 2006 1237 Research. on April 12, 2017.  To ensure that chemotoxicity attenuation is not associated with a negative effect on antitumor activity, we evaluated the activity of equal doses of irinotecan with or without methylselenocysteine (duplicated for selenomethionine) in several xenograft models (16). The addition of methylselenocysteine (or selenomethionine) was associated with an increased cure rate across all tested tumors (16). We, hereby, report the results of a phase I study of high-dose selenomethionine (2,200 Ag Se) given orally once daily in combination with escalating doses of irinotecan. The dose of selenomethionine was extrapolated from the Watchful Waiting study, a study of a high dose of selenized yeast in patients with biopsy-proven prostate cancer (17). On this study, patients were treated with 3,200 Ag/d Se in the form of selenized yeast daily for periods exceeding 1 year without the development of any serious adverse events. The speciation of the yeast used on this study showed that 70% of Se was present as a selenomethionine component. Extrapolating for the above, we considered that a 2,200 Ag dose of Se in the form of selenomethionine daily would be considered as a relatively safe dose that could be assessed as a toxicity modulator of irinotecan. Materials andMethods This phase I, open-label, dose escalation study of irinotecan in combination with a fixed dose of selenomethionine was conducted at the Roswell Park Cancer Institute (Buffalo, NY). The primary objective of the study was to determine the MTD of weekly i.v. irinotecan in combination with daily oral selenomethionine. Secondary objectives included the evaluation of pharmacokinetics of selenomethionine and irinotecan, the description of treatment-related toxicities, and the description of any observed clinical responses.