TY - JOUR
T1 - Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction
T2 - A study by the national cancer institute organ dysfunction working group
AU - Gibbons, Joseph
AU - Egorin, Merrill J.
AU - Ramanathan, Ramesh K.
AU - Fu, Pingfu
AU - Mulkerin, Daniel L.
AU - Shibata, Stephen
AU - Takimoto, Chris H.M.
AU - Mani, Sridhar
AU - LoRusso, Patricia A.
AU - Grem, Jean L.
AU - Pavlick, Anna
AU - Lenz, Heinz Josef
AU - Flick, Susan M.
AU - Reynolds, Sherrie
AU - Lagattuta, Theodore F.
AU - Parise, Robert A.
AU - Wang, Yanfeng
AU - Murgo, Anthony J.
AU - Ivy, S. Percy
AU - Remick, Scot C.
PY - 2008/2/1
Y1 - 2008/2/1
N2 - 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.
AB - 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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U2 - 10.1200/JCO.2007.13.3819
DO - 10.1200/JCO.2007.13.3819
M3 - Article
C2 - 18235116
AN - SCOPUS:39149099201
SN - 0732-183X
VL - 26
SP - 570
EP - 576
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 4
ER -