Tolerance and Pharmacokinetics of Recombinant Human Endostatin Administered as Single-Dose or Multiple-Dose Infusions in Patients With Advanced Solid Tumors: A Phase I Clinical Trial

Objective: This study aimed to investigate the tolerance and pharmacokinetic characteristics of recombinant human endostatin (rh-endostatin) administered as single-dose or multiple-dose infusions in patients with advanced solid tumors. Methods: This phase I trial was designed as a single-center, single-arm, nonrandomized, open-label, dose-escalation study. The trial consisted of 2 parts: a single-dose part and a multiple-dose part, each with 3 dose comparison groups. Rh-endostatin was administered as an intravenous injection only once at a dose of 5 mg/m(2), 7.5 mg/m(2), or 10 mg/m(2) in the single-dose part and as a daily intravenous injection for 14 days at the same doses in the multiple-dose part. The serum pharmacokinetics, toxicity and immunogenicity of rh-endostatin were evaluated. Results: Dose-limiting toxicity (DLT) was not observed in any group. A few patients developed cardiotoxicity, such as QT prolongation or narrow arrhythmia. Other adverse events were slight coagulation abnormalities and haematological abnormalities. For rh-endostatin doses of 5 mg/m(2), 7.5 mg/m(2), and 10 mg/m(2), the mean C-max values in the single-dose part were 344 +/- 38.7 ng/mL, 524 +/- 157 ng/mL, and 800 +/- 201 ng/mL, respectively, and the average AUC(0-t) values were 3290 +/- 3790 ng center dot h/mL, 4940 +/- 4380 ng center dot h/mL, and 5050 +/- 3980 ng center dot h/mL, respectively. The C-max ss values of the 3 doses in the multiple-dose part were 575 +/- 270 ng/mL, 531 +/- 106 ng/mL, and 864 +/- 166 ng/mL, respectively, and the AUC(0-tau) values were 3610 +/- 1040 ng center dot h/mL, 3290 +/- 1090 ng center dot h/mL, and 5180 +/- 1210 ng center dot h/mL, respectively. The C-max of a single-dose regimen showed linear kinetic characteristics. The patients in the single-dose group were negative for serum antibodies against rh-endostatin, while one patient in the multiple-dose group was positive. Conclusions: Rh-endostatin as a daily intravenous injection for 14 days in patients with advanced solid tumors is safe and well tolerated, without DLT, at doses of 5 mg/m(2), 7.5 mg/m(2), and 10 mg/m(2). Serum antibodies against rh-endostatin were very low after multiple infusions. For phase II trials, the recommended rh-endostatin dose is 10 mg/m(2) as a daily intravenous injection for 14 days.