Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results
| Autor: | Glenn Liu, James L. Freddo, Steven D. Reich, Yazdi K. Pithavala, John W. Park, Roy S. Herbst, George Wilding, Merrill S. Kies, Hope S. Rugo, Heidi Steinfeldt |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Adult
Male Cancer Research Indazoles Tivozanib Axitinib Maximum Tolerated Dose medicine.medical_treatment Administration Oral Angiogenesis Inhibitors Pharmacology Drug Administration Schedule Pharmacokinetics Oral administration Antacid Neoplasms Medicine Humans Drug Interactions Dosing Stomatitis Aged Neovascularization Pathologic business.industry Imidazoles Middle Aged medicine.disease Clinical trial Treatment Outcome Oncology Area Under Curve Female business medicine.drug |
| Zdroj: | Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 23(24) |
| ISSN: | 0732-183X |
| Popis: | Purpose We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. Patients and Methods Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. Results Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. Conclusion In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|