Exploration of Safety, Pharmacokinetics and Selected Pharmacodynamic Mechanisms of High-Dose Se-Methylselenocysteine, L-Selenomethionine and Selenite in a Phase Ib Trial in Cancer Patients.

High-dose selenium (Se) as selenomethionine (SLM) and sodium selenite (SS) can improve the efficacy of cancer therapies while reducing toxicity. Se-methylselenocysteine (MSC) is effective in preclinical models but has not been evaluated in cancer trials. This phase Ib randomised, double-blinded trial explored the safety, pharmacokinetics (PK) and selected pharmacodynamic (PD) mechanisms of MSC, SLM and SS to guide future trials. Nine participants with metastatic cancer took Se 1600 μg/day for 4 weeks, then 6400 μg/day for 4 weeks, as MSC, SLM, or SS, with safety, PK, and PD assessments at baseline then every 4 weeks for 12 weeks. No dose-limiting toxicities occurred, and all adverse events were grades 1-2, mainly gastrointestinal. Total plasma Se increased after 8 weeks to mean 27.2 μM with SLM, 4.14 μM with MSC and 3.90 μM with SS. No significant changes in DNA damage or intracellular glutathione were observed in peripheral blood mononuclear cells. Mean plasma selenoprotein P (SEPP) increased from 3.74 mg/L at baseline to 4.66 mg/L and 5.13 mg/L after 4 and 8 weeks (p = 0.136 and 0.104, respectively). More detailed evaluations of safety, PK and PD mechanisms are needed to determine a recommended Se compound and dose for larger trials in combination with cancer therapies.