Clinical Efficacy, Safety and Pharmacokinetics of Tracing Injection of Mitoxantrone Hydrochloride for Tracing Sentinel Lymph Nodes in Thyroid Carcinoma: A Phase Ⅰ Clinical Trial

  Objective  To investigate the staining and tracing effect of mitoxantrone hydrochloride injection for tracing lymph nodes in radical thyroidectomy, and its safety and tolerability.

  Methods  In this study, a single-centered, open-labeled, blank control trial was designed. According to the principle of dose escalation, the human tolerance test and kinetic test were performed in dose groups one by one. Patients scheduled for radical thyroidectomy in Peking Union Medical College Hospital from December 2016 to March 2017 were prospectively enrolled as subjects. The subjects were divided into the blank control group and the test groups. The blank control group routinely underwent surgery without tracer injection; the test groups were injected with 0.2 mL, 0.4 mL, 0.6 mL, 0.8 mL, or 1.2 mL of mitoxantrone hydrochloride for tracing in the thyroid gland after exposing the surgical field, and an escalation test was performed in the five dose groups from low to high. The primary efficacy measures were lymph node tracing rate and lymph node staining rate; the secondary efficacy measures were staining-degree scores of lymph nodes and the success rate of tracing persistence. Changes in signs of subjects were recorded for safety assessment. Venous blood was collected from the subjects before administration and at 10 min, 20 min, 30 min, 60 min, 90 min and 120 min after administration to calculate the kinetic parameters.

  Results  A total of 27 subjects were included, including 3 subjects in the blank control group, and 3, 3, 6, 6 and 6 subjects in the 0.2 mL, 0.4 mL, 0.6 mL, 0.8 mL and 1.2 mL dose group, respectively. When the test proceeded to the third dose group (0.6 mL), the injection site of the subjects was saturated with the injection dose, and the test was terminated. Therefore, a total of 15 subjects completed the test. No lymph node was stained in blank control group.The lymph nodes of 12 subjects showed blue staining, and the parathyroid glands were not stained and negatively visualized. There was significant difference in the staining-degree scores of lymph nodes before and after administration in the 0.2 mL, 0.4 mL and 0.6 mL dose groups (P < 0.05). The average staining rates of lymph nodes were 90.47%, 91.67% and 91.36%, respectively. And the average tracing rates of lymph nodes were 79.17%, 100% and 98.67%, respectively. In the test groups, the duration of lymph node dissection was 5-20 min; no stained lymph nodes faded, and the success rate of tracing was 100%. In the safety evaluation, no serious adverse events occurred in the blank control group and test groups, and the cause of adverse events was certainly not related to this tracer. Kinetic tests showed that the tracer was rapidly absorbed after glandular injection; the blood concentration peaked at 10 min after injection (the maximum plasma concentration was 13.1 μg/L) and it was rapidly eliminated.

  Conclusions  The use of 0.2-0.6 mL mitoxantrone hydrochloride injection in radical thyroidectomy can play a better role in tracing lymph nodes, with high safety and good tolerance.