Pharmacokinetics and dose escalation of the heat shock protein inhibitor 17-allyamino-17-demethoxygeldanamycin in combination with bortezomib in relapsed or refractory acute myeloid leukemia

Alison R. Walker, Rebecca Klisovic, Jeffrey S. Johnston, Yao Jiang, Susan Geyer, Cheryl Kefauver, Philip Binkley, John C. Byrd, Michael R. Grever, Ramiro Garzon, Mitch A. Phelps, Guido Marcucci, Kristie A. Blum, William Blum

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

This phase I study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) in combination with bortezomib, and to provide pharmacokinetic data in relapsed or refractory acute myeloid leukemia (AML). Eleven patients were enrolled. The MTD was 17-AAG 150 mg/m2 and bortezomib 0.7 mg/m2. Hepatic toxicity and cardiac toxicity were dose limiting. Co-administration on day 4 led to a decrease in clearance (p = 0.005) and increase in AUC (p = 0.032) of 17-amino-17-demethoxygeldanamycin (17-AG), not observed when 17-AAG was administered alone. Pharmacokinetic parameters of patients who developed toxicities and those who did not were not different. The combination of 17-AAG and bortezomib led to toxicity without measurable response in patients with relapsed or refractory AML. Pharmacokinetic data provide insight for studies of related agents in AML. Next-generation HSP90 inhibitors are appealing for further development in this area.

Original languageEnglish (US)
Pages (from-to)1996-2002
Number of pages7
JournalLeukemia and Lymphoma
Volume54
Issue number9
DOIs
StatePublished - Sep 2013

Keywords

  • 17-AAG
  • Bortezomib
  • Heat shock protein inhibition
  • Relapsed AML

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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