title: 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.
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/m(2)), 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/m(2) twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m(2) (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C(max) and area under the curve (AUC) from 8 to 32 mg/m(2) 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/m(2).
authors.affiliation: H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. jeffrey.lancet@moffitt.org
authors.forename: J E
authors.initials: JE
authors.lastname: Lancet
authors.forename: I
authors.initials: I
authors.lastname: Gojo
authors.forename: M
authors.initials: M
authors.lastname: Burton
authors.forename: M
authors.initials: M
authors.lastname: Quinn
authors.forename: S M
authors.initials: SM
authors.lastname: Tighe
authors.forename: K
authors.initials: K
authors.lastname: Kersey
authors.forename: Z
authors.initials: Z
authors.lastname: Zhong
authors.forename: M X
authors.initials: MX
authors.lastname: Albitar
authors.forename: K
authors.initials: K
authors.lastname: Bhalla
authors.forename: A L
authors.initials: AL
authors.lastname: Hannah
authors.forename: M R
authors.initials: MR
authors.lastname: Baer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage*; D001752:Blast Crisis; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015996:Survival Rate; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin