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

J. E. Lancet, I. Gojo, M. Burton, M. Quinn, S. M. Tighe, K. Kersey, Z. Zhong, M. X. Albitar, K. Bhalla, A. L. Hannah, M. R. Baer

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)699-705
Number of pages7
JournalLeukemia
Volume24
Issue number4
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • Alvespimycin
  • Heat shock protein 90
  • Phase I

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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