A phase I dose escalation study of AUY922, a novel HSP90 inhibitor, in patients with advanced solid malignancies
Authors: Sessa C. , Sharma S. K. , Britten C. D. , Vogelzang N. J. , Bhalla K. N. , Mita M. M. , Pluard T. J. , Stiegler P. , Quadt C. , Shapiro G. I. 
Published: August 2020

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/m2 (3pts), 4 mg/m2 (4pts), 8 mg/m2 (5pts), 16 mg/m2 (7pts), 22 mg/m2 (11pts), 28 mg/m2 (7pts) and 40 mg/m2 (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/m2. Grade 3 events, including atrial flutter, 1pt, at 22 mg/m2, anorexia, fatigue and diarrhea, 2 pts, at 40 mg/m2, 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/m2 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/m2. Prolonged disease stabilization was seen in a subset of patients receiving AUY922 across dose levels.

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