Abstract
PurposeAUY922 is a potent non-geldanamycin inhibitor of heat-shock protein 90. This study was carried out in Japanese patients to determine the maximum tolerated dose (MTD), and to characterize safety, tolerability and pharmacokinetics of single-agent AUY922.MethodsJapanese patients with advanced solid tumors whose disease had progressed on at least one line of standard therapy, or for whom no standard therapy existed, were treated with AUY922 (intravenous, once-weekly, 28-day cycle, starting dose 8 mg/m2).ResultsThirty-one patients were treated. Two DLTs were reported in one patient of the 54 mg/m2 cohort; fatigue and decreased appetite (both Grade 3, resolving to Grade 1 within 8 days). No MTD was determined, and the dose recommended for Phase II studies was determined to be 70 mg/m2 once-weekly. Most common drug-related toxicities were diarrhea, night blindness and nausea. Grade 1 and 2 visual toxicities at high AUY922 doses ≥22 mg/m2 were observed. Ten patients (32 %) achieved a best overall response of stable disease, and one patient (3 %) achieved a confirmed partial response.ConclusionOverall, AUY922 exhibited acceptable toxicities and demonstrated potential clinical activity in Japanese patients, with similar safety and pharmacokinetic profiles to those reported in a preceding global Phase I study in Western patients (CAUY922A2101).
Highlights
Overall, AUY922 exhibited acceptable toxicities and demonstrated potential clinical activity in Japanese patients, with similar safety and pharmacokinetic profiles to those reported in a preceding global Phase I study in Western patients (CAUY922A2101)
Heat-shock proteins (HSPs) are molecular chaperones that assist in the structural formation, folding and activation of a wide variety of oncogenic client proteins involved in diverse cellular processes such as apoptosis, proliferation, signal transduction and transcription control [1,2,3,4]
In a preceding global Phase I study in Western patients (CAUY922A2101), the recommended Phase
Summary
Heat-shock proteins (HSPs) are molecular chaperones that assist in the structural formation, folding and activation of a wide variety of oncogenic client proteins involved in diverse cellular processes such as apoptosis, proliferation, signal transduction and transcription control [1,2,3,4]. These client proteins include human epidermal growth factor receptor 2 (HER2), estrogen receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, vascular endothelial growth factor, AKT, c-KIT and c-MET [1, 2]. HSP90 inhibitors show synergy with various chemotherapeutic agents in murine tumor models and sensitize tumor cells to their cytotoxic effects [6,7,8]
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