title: 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: 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/m(2) and bortezomib 0.7 mg/m(2). 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.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. alison.walker@osumc.edu
authors.forename: Alison R
authors.initials: AR
authors.lastname: Walker
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klisovic
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Johnston
authors.forename: Yao
authors.initials: Y
authors.lastname: Jiang
authors.forename: Susan
authors.initials: S
authors.lastname: Geyer
authors.forename: Cheryl
authors.initials: C
authors.lastname: Kefauver
authors.forename: Philip
authors.initials: P
authors.lastname: Binkley
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: William
authors.initials: W
authors.lastname: Blum
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D011719:Pyrazines / Q000008:administration & dosage; D012008:Recurrence; D016171:Torsades de Pointes / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D016227:Benzoquinones; D001897:Boronic Acids; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C112765:tanespimycin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex