Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study.
Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study.
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DOI：
10.3390/nu7064978
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发表时间：
2015-06-19
期刊：
影响因子：
5.9
通讯作者：
Björnstedt M
中科院分区：
文献类型：
--
作者：
Brodin O;Eksborg S;Wallenberg M;Asker-Hagelberg C;Larsen EH;Mohlkert D;Lenneby-Helleday C;Jacobsson H;Linder S;Misra S;Björnstedt M
背景资料：高剂量亚硒酸钠在多种临床前恶性肿瘤模型中发挥抗肿瘤作用并增加细胞抑制药物的功效。我们在一项I期临床试验中评估了静脉注射亚硒酸钠治疗对细胞抑制药物无效的癌症患者的安全性和有效性。患者在亚硒酸盐治疗后接受一线化疗，以研究对这些药物的敏感性改变，并初步评估任何临床益处。材料与方法：34例不同耐药肿瘤患者接受亚硒酸钠静脉注射，每日1次，连续5天，连续2周或4周。每个队列包括至少三名患者，他们在整个治疗过程中接受相同的亚硒酸盐日剂量。如果0/3例患者发生剂量限制性毒性（DLT），则研究继续进行到下一个剂量水平。如果2/3发生DLT，则认为剂量过高，如果1/3发生DLT，则再纳入3例患者。剂量递增持续至达到最大耐受剂量（MTD）。MTD定义为0/3或1/6例患者发生DLT的最高剂量水平。主要终点是亚硒酸钠的安全性、剂量限制性毒性作用和MTD。次要终点为主要缓解评价。结果和结论：MTD定义为10.2 mg/m2，计算的中位血浆半衰期为18.25 h。单剂量亚硒酸盐的最大血浆硒浓度呈非线性增加。最常见的不良反应是疲劳、恶心和手指和腿抽筋。DLT为急性、持续时间短且可逆。器官功能的生物标志物表明无重大全身毒性。总之，亚硒酸钠是安全和耐受时，给药高达10.2 mg/m2，根据目前的协议。该研究的进一步发展正在进行中，以确定延长输注是否可能是更有效的治疗策略。
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.
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影响因子：
38.9
作者：
Manzanares, William;Biestro, Alberto;Hardy, Gil
通讯作者：
Hardy, Gil
影响因子：
5.6
作者：
Hoefig, Carolin S.;Renko, Kostja;Schomburg, Lutz
通讯作者：
Schomburg, Lutz
影响因子：
9.7
作者：
Luo, Hui;Yang, Yang;Xu, Caimin
通讯作者：
Xu, Caimin
影响因子：
9.7
作者：
CAFFREY, PB;FRENKEL, GD
通讯作者：
FRENKEL, GD
影响因子：
9.6
作者：
Todd, AT
通讯作者：
Todd, AT