Sessa, Cristiana, Shapiro, Geoffrey, Bhalla, Kapil, Britten, Carolyn, Jacks, Karen M, Mita, Monica, Papadimitrakopoulou, Vali, Pluard, Tim, Samuel, Thomas A., Akimov, Mikhail, Quadt, Cornelia, Fernandez-Ibarra, Cristina, Lu, Hong, Bailey, Stuart, Chica, Sandra and Banerji, Udai (2012) First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors. Journal of Clinical Oncology.

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 (PK) and pharmacodynamic (PD) profiles.
Patients and Methods
Patients with advanced solid tumors received 1-hour intravenous infusions of AUY922 once-weekly, in a 28-day cycle. An adaptive Bayesian logistic regression model, utilizing observed dose-limiting 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 a dose of 2-70 mg/m2. DLTs occurred in 8 patients (22–70 mg/m2) and included diarrhea, asthenia/fatigue, anorexia, atrial flutter, and visual symptoms. At 70 mg/m2, the AUY922 concentration achieved was consistent with active concentrations in a range of xenograft models. There was evidence of target inhibition in peripheral blood mononuclear cells (HSP70 induction) and tumor (client protein depletion and reduction of metabolic activity by 18F-FDG PET). The recommended phase 2 dose (RP2D) of 70 mg/m2 was proposed, based on toxicity, PK and PD profiles.
Conclusions
At the RP2D of 70 mg/m2, AUY922 exhibited acceptable tolerability and phase II single-agent and combination studies have been initiated in patients with HER2-positive breast, gastric, and non-small cell lung cancers.

Item Type:	Article
Keywords:	AUY922, HSP90 inhibitor, Phase I dose-escalation study
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/7676