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

Brodin O, Eksborg S, Wallenberg M, Asker-Hagelberg C, Larsen EH, Mohlkert D, Lenneby-Helleday C, Jacobsson H, Linder S, Misra S, Björnstedt M - Nutrients (2015)

Bottom Line: The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Karolinska Institutet, Karolinska University Hospital Södersjukhuset, SE-118 83 Stockholm, Sweden. ola.brodin@karolinska.se.

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.

No MeSH data available.


Related in: MedlinePlus

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).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4488827&req=5

nutrients-07-04978-f002: 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).

Mentions: The reasons to stop treatment in the four patients with selenite-induced DLT was confusion and hallucinations after four treatments in one patient at dose-level 15.3 mg/m2 due to possible interaction with a SSRI antidepressant drug (Mirtazapin); excessive fatigue and emesis after two treatments in another at the same dose-level; chest pain, anxiousness with signs of heart hypoxia on ECG and marginally increased Troponin T (but no myocardial infarction and normalized ECG within four days) in one patient; and unconsciousness, dyspnea and pronounced hypoxia with need of assisted breathing in the other, both at dose level 12.8 mg/m2 (Table 3). At higher doses, cramps of short duration in fingers and calves (similar to night cramps of the legs) and pain in the tumor were common. Garlic smell of breath was found in 15% of patients treated at dose levels of 3 mg/m2 and above. All toxicities except fatigue, a very subjective symptom, were reversible within one or two days. We did not observe any sequelae. There was no or very limited effect on routine blood tests (Figure 2). In a few patients above dose-level 6.8 mg/m2, a mild thrombocytopenia (TC count not below 80,000/mL) was found. Clinically most of the patients were euthyroid during the whole follow up period except in few patients with aberrant triiodthyronin and thyroxin values.


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

Brodin O, Eksborg S, Wallenberg M, Asker-Hagelberg C, Larsen EH, Mohlkert D, Lenneby-Helleday C, Jacobsson H, Linder S, Misra S, Björnstedt M - Nutrients (2015)

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).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488827&req=5

nutrients-07-04978-f002: 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).
Mentions: The reasons to stop treatment in the four patients with selenite-induced DLT was confusion and hallucinations after four treatments in one patient at dose-level 15.3 mg/m2 due to possible interaction with a SSRI antidepressant drug (Mirtazapin); excessive fatigue and emesis after two treatments in another at the same dose-level; chest pain, anxiousness with signs of heart hypoxia on ECG and marginally increased Troponin T (but no myocardial infarction and normalized ECG within four days) in one patient; and unconsciousness, dyspnea and pronounced hypoxia with need of assisted breathing in the other, both at dose level 12.8 mg/m2 (Table 3). At higher doses, cramps of short duration in fingers and calves (similar to night cramps of the legs) and pain in the tumor were common. Garlic smell of breath was found in 15% of patients treated at dose levels of 3 mg/m2 and above. All toxicities except fatigue, a very subjective symptom, were reversible within one or two days. We did not observe any sequelae. There was no or very limited effect on routine blood tests (Figure 2). In a few patients above dose-level 6.8 mg/m2, a mild thrombocytopenia (TC count not below 80,000/mL) was found. Clinically most of the patients were euthyroid during the whole follow up period except in few patients with aberrant triiodthyronin and thyroxin values.

Bottom Line: The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Karolinska Institutet, Karolinska University Hospital Södersjukhuset, SE-118 83 Stockholm, Sweden. ola.brodin@karolinska.se.

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.

No MeSH data available.


Related in: MedlinePlus