title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Karolinska Institutet, Karolinska University Hospital Södersjukhuset, SE-118 83 Stockholm, Sweden. ola.brodin@karolinska.se.
authors.forename: Ola
authors.initials: O
authors.lastname: Brodin
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. staffan.eksborg@karolinska.se.
authors.forename: Staffan
authors.initials: S
authors.lastname: Eksborg
authors.affiliation: Department of Laboratory Medicine, Division of Pathology F46, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. marita.wallenberg@ki.se.
authors.forename: Marita
authors.initials: M
authors.lastname: Wallenberg
authors.affiliation: Medical Products Agency, P.O. Box 26, SE-751 03 Uppsala, Sweden. charlotte.asker-hagelberg@mpa.se.|Clinical Pharmacology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Solna, SE-171 76 Stockholm, Sweden. charlotte.asker-hagelberg@mpa.se.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Asker-Hagelberg
authors.affiliation: National Food Institute, Technical University of Denmark, DK-2860 Søborg, Denmark. ehlar@food.dtu.dk.
authors.forename: Erik H
authors.initials: EH
authors.lastname: Larsen
authors.affiliation: Department of Radiology, Karolinska University Hospital Södersjukhuset, SE-171 76 Stockholm, Sweden. dag.mohlkert@sodersjukhuset.se.
authors.forename: Dag
authors.initials: D
authors.lastname: Mohlkert
authors.affiliation: Department of Oncology, Karolinska Institutet, Karolinska University Hospital Södersjukhuset, SE-118 83 Stockholm, Sweden. clara.lenneby-helleday@karolinska.se.
authors.forename: Clara
authors.initials: C
authors.lastname: Lenneby-Helleday
authors.affiliation: Department of Radiology, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. hans.jacobsson@karolinska.se.
authors.forename: Hans
authors.initials: H
authors.lastname: Jacobsson
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm SE-171 76, Sweden. Stig.Linder@ki.se.|Department of Medicine and Health, Linköping University, Linköping SE-581 83, Linköping, Sweden. Stig.Linder@ki.se.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.affiliation: Department of Laboratory Medicine, Division of Pathology F46, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. sougat.misra@ki.se.
authors.forename: Sougat
authors.initials: S
authors.lastname: Misra
authors.affiliation: Department of Laboratory Medicine, Division of Pathology F46, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. mikael.bjornstedt@ki.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Björnstedt
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D023381:Endpoint Determination; D005221:Fatigue; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea; D009369:Neoplasms / Q000188:drug therapy*; D018038:Sodium Selenite / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D018038:Sodium Selenite
keywords: carcinoma; maximum tolerated dose; pharmacokinetics; sodium selenite