Originally published as JCO Early Release 10.1200/JCO.2005.04.192 on July 18 2005

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Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results

From the University of California, San Francisco Comprehensive Cancer Center, San Francisco; Pfizer Global Research and Development, San Diego, CA; University of Wisconsin Comprehensive Cancer Center, Madison, WI; The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to George Wilding, MD, University of Wisconsin Comprehensive Cancer Center, K4/610 CSC, 600 Highland Ave, Madison, WI 53792; e-mail: gxw{at}medicine.wisc.edu

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.

Research support provided by Pfizer Global Research and Development, San Diego, CA, and Groton, CT.

Presented at the American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics, 2003, Boston, MA; 6th International Symposium on Antiangiogenesis Agents, 2004, San Diego, CA; and American Society of Clinical Oncology Annual Meeting, 2004, New Orleans, LA.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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