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Clinical Trial
. 2021 Jan-Dec:20:15330338211064434.
doi: 10.1177/15330338211064434.

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

Xu Wang  1   2   3   4 , Yehui Shi  1   2   3   4 , Yongsheng Jia  1   2   3   4 , Weipeng Zhao  1   2   3   4 , Li Zhang  1   2   3   4 , Guiying Bai  1   2   3   4 , Yulin Ren  1   2   3   4 , Yong-Zi Chen  2   3   4   5 , Zhongsheng Tong  1   2   3   4
Affiliations
Clinical Trial

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

Xu Wang et al. Technol Cancer Res Treat. 2021 Jan-Dec.

Abstract

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/m2, 7.5 mg/m2, or 10 mg/m2 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/m2, 7.5 mg/m2, and 10 mg/m2, the mean Cmax 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 AUC0-t values were 3290 ± 3790 ng•h/mL, 4940 ± 4380 ng•h/mL, and 5050 ± 3980 ng•h/mL, respectively. The Cmax 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 AUC0-τ values were 3610 ± 1040 ng•h/mL, 3290 ± 1090 ng•h/mL, and 5180 ± 1210 ng•h/mL, respectively. The Cmax 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/m2, 7.5 mg/m2, and 10 mg/m2. Serum antibodies against rh-endostatin were very low after multiple infusions. For phase II trials, the recommended rh-endostatin dose is 10 mg/m2 as a daily intravenous injection for 14 days.

Keywords: angiogenesis; pharmacokinetics dose-limiting toxicity; phase I clinical trial; rh-endostatin.

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Conflict of interest statement

Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
The 8-h linear curve showing the mean blood concentration of rh-endostatin over time in the single-dose part of the study (A); the Cmax (B) and AUC0-t (C) in each single-dose group.
Figure 2.
Figure 2.
Mean blood concentration-time curves in the 5-mg/m2 group (A), 7.5-mg/m2 group (B), and 10-mg/m2 group (C) in the multiple-dose part of the study.
Figure 3.
Figure 3.
Cmax (A) and AUC (B) on day 1 and day 14 in each multiple-dose group.
See this image and copyright information in PMC

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