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

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.

Keywords::

• Relapsed AML
• bortezomib
• 17-AAG
• heat shock protein inhibition

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

This work was supported by: NIH/NCI K23CA120708 (W.B.), K12CA133250 (J.C.B. and A.W.) NIH/NCI U01CA76576 (M.R.G.), K23CA109004 (K.B.) and a CALGB Young Investigator Award (K.B.). A.W. is a Paul Calabresi Clinical Scholar and a scholar of the American Society of Hematology-Amos Medical Faculty Development Program.

NCI Clinical Trials Network registration: NCT00103272.