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.

Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE

Publication: 2000- : London : Nature Publishing Group, Specialist Journals
Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987-

Antineoplastic Agents/*therapeutic use ; Benzoquinones/*administration & dosage ; HSP90 Heat-Shock Proteins/*antagonists & inhibitors ; Lactams, Macrocyclic/*administration & dosage ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy ; Leukemia, Myeloid, Acute/*drug therapy; Aged ; Aged, 80 and over ; Apoptosis/drug effects ; Blast Crisis ; Female ; HSP70 Heat-Shock Proteins/antagonists & inhibitors ; HSP70 Heat-Shock Proteins/metabolism ; Humans ; Infusions, Intravenous ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Male ; Maximum Tolerated Dose ; Middle Aged ; Survival Rate ; Treatment Outcome ; Tumor Cells, Cultured

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).

0 (Antineoplastic Agents)
0 (Benzoquinones)
0 (HSP70 Heat-Shock Proteins)
0 (HSP90 Heat-Shock Proteins)
0 (Lactams, Macrocyclic)
001L2FE0M3 (17-(dimethylaminoethylamino)-17-demethoxygeldanamycin)

Date Created: 20100130 Date Completed: 20100520 Latest Revision: 20130304

20250114

10.1038/leu.2009.292

20111068