Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia.
In: Leukemia (08876924), Jg. 24 (2010-04-01), Heft 4, S. 699-705
Online
academicJournal
Zugriff:
Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8–32 mg/m2), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m2 twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m2 (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in Cmax and area under the curve (AUC) from 8 to 32 mg/m2 and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twice-weekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m2. [ABSTRACT FROM AUTHOR]
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Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia.
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Autor/in / Beteiligte Person: | Lancet, J. E. ; Gojo, I. ; Burton, M. ; Quinn, M. ; Tighe, S. M. ; Kersey, K. ; Zhong, Z. ; Albitar, M. X. ; Bhalla, K. ; Hannah, A. L. ; Baer, M. R. |
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Zeitschrift: | Leukemia (08876924), Jg. 24 (2010-04-01), Heft 4, S. 699-705 |
Veröffentlichung: | 2010 |
Medientyp: | academicJournal |
ISSN: | 0887-6924 (print) |
DOI: | 10.1038/leu.2009.292 |
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