Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 26, Issue 4, Pages 570-576Publisher
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2007.13.3819
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Funding
- NCI NIH HHS [5U01CA069853, U01 CA062502, P30 CA43703, U01 CA062491, P30 CA043703, U01 CA62502, 5 U01 CA62505, U01 CA099168, P30 CA47904] Funding Source: Medline
- NCRR NIH HHS [M01 RR-000080, 5M01 RR-00056] Funding Source: Medline
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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] >= 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. 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.
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