AUY922, a novel HSP90 inhibitor: Final results of a first-in-human study in patients with advanced solid malignancies.

Abstract

2528 Background: AUY922, a novel isoxazole-based HSP90 inhibitor, causes the degradation of multiple oncogenic cellular proteins and preclinical data suggest broad antitumor activity. Methods: Single agent AUY922 was administered as IV infusion over 1h, once weekly, to patients (pts) with advanced solid tumors to determine the maximum tolerated dose (MTD) in a phase I study. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Endpoints included safety, tolerability, preliminary activity, PK, and PD. Results: 96 pts received AUY922 at doses of 2–70 mg/m2 (23 pts at 70 mg/m2). Pt characteristics: median age 57 yrs, 96% WHO performance status 0 or 1, 41% male, and 82% Caucasian. The most frequently reported adverse events possibly related to AUY922 were diarrhea in 53 pts (55%), nausea in 34 pts (35%), fatigue in 31 pts (32%), night blindness in 19 pts (20%), and vomiting in 18 pts (19%). Visual symptoms (mainly grade 1–2 and mostly reversible) including blurred vision, flashing, and delayed dark/light accommodation were reported starting at 40 mg/m2, and increased in frequency or severity with dose. Dose limiting toxicities, all grade 3, included atrial flutter (22 mg/m2), anorexia, fatigue, and diarrhea (40 mg/m2), asthenia and diarrhea (54 mg/m2) and diarrhea and darkening of vision (70 mg/m2). The MTD was 70 mg/m2. Median duration of exposure was 7.0 weeks (range; 1, 80). Disease stabilization was reported in 16 pts and 9 pts reported partial metabolic response in FDG-PET scans. AUY922 blood concentration followed a bi-exponential decline with a fast a phase (t1/2 <10 min) and a slow β phase (t1/2 ∼60h). Dose-related induction of HSP70, indicating inhibition of HSP90, was seen. A phase II expansion study in pts with advanced breast cancer (HER2+ and ER+) has begun. Conclusions: Weekly IV infusion of single agent AUY922 was well tolerated at the MTD of 70 mg/m2. Disease stabilization was seen in a subset of pts receiving AUY922. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, The Institute of Cancer Research Novartis GlaxoSmithKline, Novartis, sanofi-aventis Novartis, Exelesis, Infinity Pharmaceuticals, Pfizer, Wyeth