Originally published as JCO Early Release 10.1200/JCO.2005.04.143 on July 18 2005

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Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

From the University of Wisconsin Comprehensive Cancer Center, Madison, WI; University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Pfizer Global Research and Development, La Jolla, CA, Groton, CT, and Ann Arbor, MI; and VirtualScopics LLC, Rochester, NY

Address reprint requests to Roy S. Herbst, MD, PhD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030; e-mail: rherbst{at}mdanderson.org

PURPOSE: Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

PATIENTS AND METHODS: Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1—day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K^trans) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function.

RESULTS: Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K^trans and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a 50% decrease in K^trans was indicative of an objective vascular response, a 50% decrease in K^trans was achieved and corresponded to a plasma AUC_0-24 of > 200 ng · h/mL.

CONCLUSION: A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.

Supported by 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, November 17-21, 2003, Boston, MA; 6th International Symposium on Antiangiogenesis Agents, January 30-February 1, 2004, San Diego, CA; American Society of Clinical Oncology Annual Meeting, June 5-8, 2004, New Orleans, LA; and International Society of Magnetic Resonance in Medicine, May 15-21, 2004, Kyoto, Japan.

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

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