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 language | English (US) |
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Pages (from-to) | 1996-2002 |
Number of pages | 7 |
Journal | Leukemia and Lymphoma |
Volume | 54 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2013 |
Keywords
- 17-AAG
- Bortezomib
- Heat shock protein inhibition
- Relapsed AML
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research