Related Experiment Videos
Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid
James P Thomas1, Rhoda Z Arzoomanian, Dona Alberti
1Department of Medicine, Section of Medical Oncology and University of Wisconsin Comprehensive Cancer Center, University of Wisconsin Medical School, Madison, 53792, USA.
Purpose:
Endostatin is the first endogenous angiogenesis inhibitor to enter clinical trials. Laboratory investigations with endostatin have indicated broad antitumor activity coupled with remarkably low toxicity. A phase I trial of recombinant human endostatin was designed to evaluate toxicity and explore biologic effectiveness in patients with refractory solid tumors.
Patients And Methods:
Endostatin was administered as a 1-hour intravenous infusion given daily for a 28-day cycle. A starting dose of 30 mg/m2 was explored with subsequent dose escalations of 60, 100, 150, 225, and 300 mg/m2. Assessment of serum pharmacokinetics was performed on all 21 patients. Western blot assay and mass spectroscopy were employed to evaluate endostatin metabolism. Circulating levels of endogenous proangiogenic growth factors were examined. Tumor and tumor blood supply were imaged by dynamic computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography.
Results:
Endostatin given on this schedule was essentially free of significant drug-related toxicity. Two transient episodes of grade 1 rash were observed. No clinical responses were observed. Endostatin pharmacokinetics were linear with dose, and serum concentrations were achieved that are associated with antitumor activity in preclinical models. No aggregate effect on circulating proangiogenic growth factors were seen, although several patients exhibited persistent declines in vascular endothelial growth factor levels while enrolled in the study. A few patients demonstrated changes in their dynamic CT scans suggestive of a decline in microvessel density, although overall, no consistent effect of endostatin on tumor vasculature was seen.
Conclusion:
Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m2.
Insights
This phase I trial found that endostatin, an endogenous angiogenesis inhibitor, was well-tolerated in patients with refractory solid tumors. Daily intravenous infusions up to 300 mg/m2 showed no dose-limiting toxicity but did not demonstrate clinical responses.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Endostatin is an endogenous angiogenesis inhibitor with preclinical antitumor activity and low toxicity.
- It was the first endogenous angiogenesis inhibitor to enter clinical trials.
- Phase I trials are crucial for evaluating the safety and biologic effectiveness of novel cancer therapeutics.
Purpose of the Study:
- To evaluate the toxicity of recombinant human endostatin in patients with refractory solid tumors.
- To explore the biologic effectiveness of endostatin in this patient population.
- To determine the maximum tolerated dose and dose-limiting toxicities of endostatin.
Main Methods:
- Administered endostatin as a 1-hour intravenous infusion daily for 28-day cycles.
- Dose escalation from 30 mg/m2 to 300 mg/m2 across 21 patients.
- Assessed pharmacokinetics, metabolism, proangiogenic factors, and tumor vasculature using various imaging techniques.
Main Results:
- Endostatin was well-tolerated with minimal toxicity (grade 1 rash).
- No clinical responses were observed in patients.
- Pharmacokinetics were linear, achieving concentrations associated with preclinical antitumor activity, but no consistent effect on tumor vasculature was seen.
Conclusions:
- Daily intravenous endostatin infusions up to 300 mg/m2 were safe and well-tolerated.
- The study did not demonstrate clinical efficacy or consistent anti-angiogenic effects in patients with refractory solid tumors.
- Further investigation may be needed to optimize endostatin's therapeutic application.