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

Abstract

Purpose: A phase I study was conducted with the primary objective of determining the maximum tolerated dose (MTD) of AUY922 in patients with advanced solid tumors. Secondary objectives included characterization of the safety, pharmacokinetic, and pharmacodynamic profiles.Patients and Methods: Patients with advanced solid tumors received 1-hour i.v. infusions of AUY922 once a week in a 28-day cycle. An adaptive Bayesian logistic regression model that employed observed doselimiting toxicities (DLT) in the first treatment cycle was used to guide dose-escalation decisions, with the established MTD to be used in phase II studies.Results: One hundred and one patients were enrolled and explored at doses in the range of 2 to 70 mg/m

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

“…TAS-116 addresses the issues that have hampered the clinical development of HSP90 inhibitors because it shows a favorable tissue distribution profile. One of the most notable HSP90-related adverse events universally observed but to differing degrees in the clinic is visual disturbance (18)(19)(20)(21)(45)(46)(47)(48). The observed symptoms include night blindness, photopsia, blurred vision, and visual impairment, which are likely associated with retinal dysfunction (20,21).…”

“…Therefore, we evaluated the tissue distribution profile and ocular toxicity of TAS-116 in rats bearing subcutaneous human tumors (NCI-H1975). NVP-AUY922 was used as the reference compound because visual impairment was frequently observed in a phase I study of this compound (21). After administration of NVP-AUY922 intravenously or TAS-116 orally, plasma, retina, and tumor samples were collected and the concentration of each compound in the tissues was determined.…”

“…For example, neurological toxicities such as syncope and dizziness were seen in a phase I trial of the purine analogue BIIB021 (17), although there is no evidence to support this to be target or purine-scaffold related. In clinical trials of other HSP90 inhibitors, the most commonly observed HSP90-related adverse events have been visual disorders such as night blindness, photopsia, blurred vision, and visual impairment, though the frequency and degree varied among the compounds (18)(19)(20)(21). For example, 43% of patients suffered visual disturbances in a phase I trial of NVP-AUY922 (21).…”

“…In clinical trials of other HSP90 inhibitors, the most commonly observed HSP90-related adverse events have been visual disorders such as night blindness, photopsia, blurred vision, and visual impairment, though the frequency and degree varied among the compounds (18)(19)(20)(21). For example, 43% of patients suffered visual disturbances in a phase I trial of NVP-AUY922 (21). Though HSP90-related visual disorders, which have included grade 3 events, are reversible (21), these adverse events interfere with obtaining sufficient drug exposure because of drug interruption or discontinuation, or dose reduction.…”

“…For example, 43% of patients suffered visual disturbances in a phase I trial of NVP-AUY922 (21). Though HSP90-related visual disorders, which have included grade 3 events, are reversible (21), these adverse events interfere with obtaining sufficient drug exposure because of drug interruption or discontinuation, or dose reduction.…”