| Objective:To investigate the tolerance and pharmacokinetic profile of recombinant human endostatin administered as single-dose and multiple-dose injection in patients with advanced solid tumors.Methods:This phase I trial was designed as single-center,single-arm,non-randomized,open-label,dose escalation study.The trail was divided into two parts,the single-dose group and the multiple-dose group.Recombinant human endostatin was administered as a 120 minute intravenous injection only once at dose of 5mg/m~2?7.5mg/m~2?10mg/m~2 in the single-dose group,and was administered as a120 minute intravenous daily injection for 14 day at the same dose in the multiple-dose group.In each dose group,6-8 patients with advanced solid tumors were enrolled.Serum rh-endostatin pharmacokinetics,toxicity and circulating antibodies to endostatin were determined.Results:The dose limited toxicity was not observed in all groups,a few patients had cardiotoxicity,such as: QT prolongation or narrow,arrhythmia.Other adverse events were slightly coagulation abnormality,hematology abnormality.The mean Cmax in the single-dose group was 344±38.7 ng/m L,524±157 ng/m L,800±201 ng/m L,and the average AUC0-t was 3290±3790 h·ng/m L,4940±4380 h,and 5050±3980 h·ng/m L.The Cmax ss of multiple-dose group were 575±270 ng/m L,531±106 ng/m L,864±166 ng/m L,and AUC0-? were 3610±1040 h·ng/m L,3290±1090 h·ng/m L,5180±1210 h·ng/m L.Serum antibodies to endostatin was negative in the single-dose group,and one patient in the multiple-dose group was positive for the serum antibodies to endostatin.Conclusion:Recombinant human endostatin administered as daily for 14 day continue intravenous injection in patients with advanced solid tumors was safety and well tolerated without dose limited toxicity at dose of 5mg/m~2?7.5mg/m~2?10mg/m~2.The Cmax of single-dose group showed linear kinetic characteristics.The Cmax ss and AUC of multiple-dose group increased with dose escalation.The serum antibodies to endostatin after multiple dose administration was very low.The clinical dose of 10mg/m~2 daily for 14 days continue intravenous injection in phase ? trialis recommend. |
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