Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study

Abstract

Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients’ refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m2, with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m2 under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

Combination of carmustine and selenite effectively inhibits tumor growth by targeting androgen receptor, androgen receptor‐variants, and Akt in preclinical models: New hope for patients with castration resistant prostate cancer

“…For in vivo mouse xenograft studies 1.5 mg selenite/kg body weight and 20 mg carmustine/kg body weight were selected for use in combination. The dose of 1.5 mg of selenite/kg body weight in mouse translates to 4.44 mg/m 2 in humans and is less than the maximal tolerance dose of selenite shown in phase‐1 clinical trials (10.2 mg/m 2 ) . Similarly, the dose of 20 mg of carmustine/kg body weight in mouse translates to 59.9 mg/m 2 in humans, less than the dose used in phase‐1 clinical trials (450 mg/m 2 ) .…”

Selenium in Cardiac Surgery

“…Notably, high concentrations of sodium selenite, such as 10 g, might be associated with severe adverse events such as vomiting, nausea, severe headache, nail discoloration or brittleness, hair loss, or fatigue, whereas no adverse effects have yet been reported in any of the clinical studies that have been performed with Se . A recent intervention trial with patients with cancer has indicated that the total amounts of Se that can be tolerated without severe adverse effects are indeed in the mg range . Given these aspects about the right form of application and the clinical findings reported in the most recent meta‐analysis, the most adequate supplementation strategy is still unknown and may differ among clinical scenarios.…”

Biolog phenotype microarray: a tool for the identification of multidrug resistance efflux pumps inducers

“…This is a fact to take into account regarding clinical situations, since some of these inducer molecules could be provided during a S. maltophilia infection treatment. For instance, sodium selenite has been recently administered during a phase I clinical trial in terminal cancer patients (58) due to its cytotoxic effect on proliferating cancer cells. Since these patients are delicately vulnerable to infections caused by MDR Gram-negative bacteria, such as S. maltophilia (59), the dispensation of sodium selenite could lead to the overexpression of smeVWX and thus, transient resistance to its substrates.…”