A phase I clinical trial for recombinant human endostatin

Abstract

Objective:To determine the maximum tolerated dose (MTD) and the pharmacoki-netics of the endostatin (rh-endostatin, YH-16) injection in human. Methods: 12 healthy volunteers were equally divided into 4 groups. Each group was intravenously administrated with a single dose of YH-16 infusion at 30,60,120 and 210mg·m-2,respectively. 10 patients with advanced solid tumors were categorized into 3 groups (4,3 and 3 patients per group). Each group was intravenously given with a dose of YH-16 infusion at 7.5,15 and 30mg·m-2 once daily for 28 days, respectively. The YH-16 concentration in serum sampes from all subjects was analyzed by ELISA,so as to determine the pharmacokinetic profile. Results:The dose limiting toxicities (DLT) were measured as varieties of car-diac adverse reactions, including sinus arrhythmia, supraventricular tachycardia, ventricular premature beat and T wave changes shown in electrocardiogram. The other mild adverse events were found to be fever,rash, minor dizziness, headache, fatigue, palpitation, chest discomfort and diarrhea. One patient with malignant melanoma had a minor response and 5 patients showed stable disease.The pharmacokinetic disposition was almost linear in healthy volunteers. However,the individual difference on concentration vs. time was observed in patients with advanced solid tumors. Conclusion:The YH-16 was clini-cally tolerated well.The MTD was 120mg·m-2 in healthy volunteers with a single dose, and 15mg· m-2 in the tumor patients with a daily dose for 28 days. The efficacy of anti-tumor with YH-16 was evident.The clinical dosage of 12mg·m-2 daily for 28 days in phase Ⅱ study is recommended.