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Journal of Clinical Oncology, Vol 26, No 4 (February 1), 2008: pp. 570-576 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.3819 Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group
From the Developmental Therapeutics Program, Case Comprehensive Cancer Center, Ireland Cancer Center at University Hospitals of Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH; University of Pittsburgh Cancer Institute, Pittsburgh, PA; University of Wisconsin Comprehensive Cancer Center, Madison, WI; City of Hope National Medical Center, Duarte; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; University of Texas Health Science Center, San Antonio, TX; Albert Einstein College of Medicine, Bronx; Kaplan Comprehensive Cancer Center, New York University, New York, NY; Wayne State University, Detroit, MI; National Cancer Institute, Medicine Branch, National Naval Medical Center, Bethesda; Center for Treatment and Evaluation Program, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Rockville, MD; and Novartis Pharmaceuticals, Florham Park, NJ Corresponding author: Scot C. Remick, MD, Mary Babb Randolph Cancer Center, West Virginia University, 1801 Health Sciences South, PO Box 9300, Morgantown, WV 26506; e-mail: sremick{at}hsc.wvu.edu Purpose This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients.
Patients and Methods Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] Results The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose. Conclusion Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure. Supported by National Institutes of Health Grants No. U01 CA62502, M01 RR-000080, P30 CA43703, U01 CA099168, 5M01 RR-00056, P30 CA47904, 5 U01 CA62505, U01 CA062491, and 5U01CA069853 and Translational Research Initiative Contract No. 22XS041A. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003 Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long. 
