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

Joseph Gibbons, Merrill J. Egorin, Ramesk K Ramanathan, Pingfu Fu, Daniel L. Mulkerin, Stephen Shibata, Chris H M Takimoto, Sridhar Mani, Patricia A. LoRusso, Jean L. Grem, Anna Pavlick, Heinz Josef Lenz, Susan M. Flick, Sherrie Reynolds, Theodore F. Lagattuta, Robert A. Parise, Yanfeng Wang, Anthony J. Murgo, S. Percy Ivy, Scot C. Remick

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)570-576
Number of pages7
JournalJournal of Clinical Oncology
Volume26
Issue number4
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

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National Cancer Institute (U.S.)
Pharmacokinetics
Kidney
Neoplasms
Creatinine
Maximum Tolerated Dose
Imatinib Mesylate
Orosomucoid
Area Under Curve
Glycoproteins
Guidelines
Safety
Acids

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

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. / Gibbons, Joseph; Egorin, Merrill J.; Ramanathan, Ramesk K; Fu, Pingfu; Mulkerin, Daniel L.; Shibata, Stephen; Takimoto, Chris H M; Mani, Sridhar; LoRusso, Patricia A.; Grem, Jean L.; Pavlick, Anna; Lenz, Heinz Josef; Flick, Susan M.; Reynolds, Sherrie; Lagattuta, Theodore F.; Parise, Robert A.; Wang, Yanfeng; Murgo, Anthony J.; Ivy, S. Percy; Remick, Scot C.

In: Journal of Clinical Oncology, Vol. 26, No. 4, 01.02.2008, p. 570-576.

Research output: Contribution to journalArticle

Gibbons, J, Egorin, MJ, Ramanathan, RK, Fu, P, Mulkerin, DL, Shibata, S, Takimoto, CHM, Mani, S, LoRusso, PA, Grem, JL, Pavlick, A, Lenz, HJ, Flick, SM, Reynolds, S, Lagattuta, TF, Parise, RA, Wang, Y, Murgo, AJ, Ivy, SP & Remick, SC 2008, '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', Journal of Clinical Oncology, vol. 26, no. 4, pp. 570-576. https://doi.org/10.1200/JCO.2007.13.3819
Gibbons, Joseph ; Egorin, Merrill J. ; Ramanathan, Ramesk K ; Fu, Pingfu ; Mulkerin, Daniel L. ; Shibata, Stephen ; Takimoto, Chris H M ; Mani, Sridhar ; LoRusso, Patricia A. ; Grem, Jean L. ; Pavlick, Anna ; Lenz, Heinz Josef ; Flick, Susan M. ; Reynolds, Sherrie ; Lagattuta, Theodore F. ; Parise, Robert A. ; Wang, Yanfeng ; Murgo, Anthony J. ; Ivy, S. Percy ; Remick, Scot C. / 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. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 4. pp. 570-576.
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abstract = "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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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, Ramesk 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.

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JO - Journal of Clinical Oncology

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