A phase I dose escalation study of AUY922, a novel HSP90 inhibitor, in patients with advanced solid malignancies
Authors: C. Sessa, S. K. Sharma, C. D. Britten, N. J. Vogelzang, K. N. Bhalla, M. M. Mita, T. J. Pluard, P. Stiegler, C. Quadt, G. I. Shapiro
Journal: Journal of Clinical Oncology (2009)

3532^ Background: AUY922, a novel isoxazole-based HSP90 inhibitor, causes the degradation of multiple cellular tumor promoting targets. Preclinical evidence suggests broad anti-tumor activity of AUY922, warranting clinical development. Methods: Single agent AUY922 was administered as IV infusion over 1h once a week to patients (pts) with advanced solid malignancies, utilizing a Bayesian design for dose-escalation. The primary endpoint was determination of the maximum tolerated dose of AUY922; secondary endpoints included safety, tolerability, preliminary activity, PK and PD. Results: Between Jul 2007 and Dec 2008, 44 pts with were treated at dose levels of 2 mg/m 2 (3pts), 4 mg/m 2 (4pts), 8 mg/m 2 (5pts), 16 mg/m 2 (7pts), 22 mg/m 2 (11pts), 28 mg/m 2 (7pts) and 40 mg/m 2 (7pts). Median age was 56 years; 95% of pts had a WHO performance status 0 or 1. The most frequently reported adverse events were nausea in 19 patients (50.0 %), diarrhea in 18 patients (47.4 %), fatigue in 15 patients (39.5 %), and vomiting in 9 patients (23.7 %). Grade 1 and 2 diarrhea, fatigue, nausea and vomiting were suspected to be related to AUY922 at doses ≥ 8 mg/m 2 . Grade 3 events, including atrial flutter, 1pt, at 22 mg/m 2 , anorexia, fatigue and diarrhea, 2 pts, at 40 mg/m 2 , were reported as dose limiting toxicities. Expansion of the 40 mg/m2 cohort was initiated in Dec 2008. The median terminal half life of AUY922 at doses up to 28 mg/m 2 was 56 h (24 to 108 h). Pharmacodynamic analyses show dose proportional induction of HSP70 in peripheral blood mononuclear cells by AUY922. Six pts achieved disease stabilization for at least 16 and up to 64 weeks. Conclusions: Single-agent AUY922, administered as a weekly infusion, is well tolerated at doses up to 40 mg/m 2 . Prolonged disease stabilization was seen in a subset of patients receiving AUY922 across dose levels. [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .