Phase I dose-escalation study of the highly potent VEGF receptor kinase inhibitor, AZD2171, in patients with advanced cancers with liver metastases

Abstract

3055 Background: Antiangiogenic therapy is a promising strategy to inhibit tumor growth and the formation of metastases. Vascular endothelial growth factor (VEGF) is a key proangiogenic factor essential for the development of new tumor blood vessels. AZD2171 is an orally available, highly potent inhibitor of VEGF receptor tyrosine kinase that has been assessed in a Phase I study of patients with advanced cancer and liver metastases. This study was designed to evaluate the safety and tolerability of ascending doses of AZD2171. Additional assessment of pharmacokinetics (PK), surrogate markers of activity and antitumor effects was also made. Methods: Cohorts of three patients received a single oral dose of AZD2171 (0.5, 1, 2.5, 5 or 10 mg p.o.) followed by a 7-day washout period and then received daily dosing at the same dose for a total of 28 days. Further 28-day treatment cycles were administered until a withdrawal criterion was met. Results: To date, 16 patients with advanced cancers and liver metastases (9 female, 7 male, median age 57 years) have been treated with AZD2171. Preliminary PK data indicate that AZD2171 is rapidly absorbed with a median time to maximal plasma concentration of 3.0 hours and a grand arithmetic mean terminal phase half-life of 20 hours. The exposure observed following continuous once-daily dosing for 28 days was entirely consistent with the terminal phase half-life obtained after a single oral dose. The PK profile appears to be linear following single and multiple doses. Treatment was well tolerated at the dose levels evaluated and the MTD has not been established. In the 10 mg cohort, one patient developed CTC grade 2 dizziness. No other drug-related toxicities have been observed. Conclusion: Continuous, once-daily, oral treatment with the highly potent VEGF receptor tyrosine kinase inhibitor, AZD2171, was well tolerated in this ongoing Phase I study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; ProQinase AstraZeneca