First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors

摘要: Purpose: A phase I study was conducted with the primary objective of determining maximum tolerated dose (MTD) AUY922 in patients advanced solid tumors. Secondary objectives included characterization safety, pharmacokinetic, and pharmacodynamic profiles. Patients Methods: tumors received 1-hour i.v. infusions once a week 28-day cycle. An adaptive Bayesian logistic regression model that employed observed dose-limiting toxicities (DLT) first treatment cycle used to guide dose-escalation decisions, established MTD be II studies. Results: One hundred one were enrolled explored at doses range 2 70 mg/m . DLTs occurred 8 (22–70 ) diarrhea, asthenia/fatigue, anorexia, atrial flutter, visual symptoms. At , concentration achieved consistent active concentrations xenograft models. There evidence target inhibition peripheral blood mononuclear cells (HSP70 induction) tumor (client protein depletion reduction metabolic activity by 18 F-FDG PET). The recommended (RP2D) proposed on basis toxicity pharmacokinetic Conclusions: RP2D exhibited acceptable tolerability, single-agent combination studies have been initiated HER2-positive breast, gastric, non–small cell lung cancers. Clin Cancer Res; 19(13); 3671–80. ©2013 AACR