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Clinical Trial
. 2015 Jun 19;7(6):4978-94.
doi: 10.3390/nu7064978.

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

Ola Brodin  1 , Staffan Eksborg  2 , Marita Wallenberg  3 , Charlotte Asker-Hagelberg  4   5 , Erik H Larsen  6 , Dag Mohlkert  7 , Clara Lenneby-Helleday  8 , Hans Jacobsson  9 , Stig Linder  10   11 , Sougat Misra  12 , Mikael Björnstedt  13
Affiliations
Clinical Trial

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

Ola Brodin et al. Nutrients. .

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/m(2), 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/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

Keywords: carcinoma; maximum tolerated dose; pharmacokinetics; sodium selenite.

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Figures

Figure 1
Figure 1
Schematic diagram depicting the study design. The first 13 patients were treated as per the initial study protocol that was amended and Patients 14–34 were subjected to new treatment schedule. For detailed information on the specific chemotherapeutic interventions in each patient, please refer to Supplementary Table S1. 160 × 41 mm (300 × 300 DPI).
Figure 2
Figure 2
Routine blood parameters in patients during the course of the treatment as a measure of systemic toxicity. Abbreviations: WBC—white blood cell count; TC—thrombocytes count; AST—aspartate amino transferase; ALT—alanine amino transferase; ALP—alkaline phosphatase; and LDH—lactate dehydrogenase. 155 × 131mm (300 × 300 DPI).
Figure 3
Figure 3
(A) Plasma selenium concentration in different cohorts receiving increasing concentration of sodium selenite during the first two-weeks of treatment. (B) Plasma selenium concentration–time curve in Patient 9. The daily dose (1.5 mg/m2) was given as a 20 min constant rate infusion. Start of infusions is indicated by the vertical lines. Measured serum concentrations are given by the filled circles. (C,D) Systemic selenium exposure is expressed as area under the serum concentration–time curve (µM*h). Figure 3C shows data from a single dose of selenite and data from the entire treatment period are presented in Figure 3D. (E,F) Figure 3E represent maximum concentration of selenium after a single dose of selenite. Maximum concentration of selenium during the entire treatment period is presented in Figure 3F. (G) Elimination half-life of selenium at different doses. In all the figures, filled circles indicate data from 20 min infusions and open circles data from 40 min infusions. Abbreviations: BI—before injection; AI—after injection; AUC—area under curve; and Cmax—maximum concentration 162 × 253mm (300 × 300 DPI).
Figure 3
Figure 3
(A) Plasma selenium concentration in different cohorts receiving increasing concentration of sodium selenite during the first two-weeks of treatment. (B) Plasma selenium concentration–time curve in Patient 9. The daily dose (1.5 mg/m2) was given as a 20 min constant rate infusion. Start of infusions is indicated by the vertical lines. Measured serum concentrations are given by the filled circles. (C,D) Systemic selenium exposure is expressed as area under the serum concentration–time curve (µM*h). Figure 3C shows data from a single dose of selenite and data from the entire treatment period are presented in Figure 3D. (E,F) Figure 3E represent maximum concentration of selenium after a single dose of selenite. Maximum concentration of selenium during the entire treatment period is presented in Figure 3F. (G) Elimination half-life of selenium at different doses. In all the figures, filled circles indicate data from 20 min infusions and open circles data from 40 min infusions. Abbreviations: BI—before injection; AI—after injection; AUC—area under curve; and Cmax—maximum concentration 162 × 253mm (300 × 300 DPI).
Figure 4
Figure 4
(A) Waterfall plot showing tumor response following selenite treatment (top panel) and subsequent administration of chemotherapeutic drugs (bottom panel). In the waterfall plot, a positive value indicates increase in tumor volume and vice versa. (B) Anterior-posterior Maximum Intensity Projection (MIP) PET images of a 48 year old man with multiple metastases from a carcinoma of the left sinus ethmoidalis, acquired 60 min after iv administration of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) (4 MBq/kg body weight); left panel, baseline examination; and right panel, examination after 17 days following stopping his selenite treatment (three treatments with 28.2 mg selenite a day). A few hours after the first treatment, his primary tumor, localized behind his left eye, started to swell, producing a massive increase of his earlier modest exophthalmos. However, it returned to the earlier status after 1–2 days. This examination shows a general decrease of the FDG-uptake of the metastases, most evident in a large metastasis of the left liver lobe (arrow). (C) Toxicity of single or combined exposure of carboplatin and gemcitabine for 48 h to cells collected from pleural exudates from a patient. Fraction 1 indicates before selenite treatment and Fraction 2 indicates after selenite treatment. Data are presented as mean ± S.D. 160 × 143 mm (300 × 300 DPI).
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