Abstract B98: AUY922, a novel HSP90 inhibitor: Final results of a phase I dose escalation study in Japanese patients with advanced solid malignancies.

Background: AUY922 is a novel, highly potent, non-geldanamycin HSP90 inhibitor, which causes the degradation of multiple oncogenic cellular proteins, and has been suggested to have potential clinical activity in an earlier global Phase I study and ongoing global Phase II studies.

Methods: Single agent AUY922 was administered as a 1 hour weekly IV infusion to Japanese patients (pts) with advanced solid malignancies, This Phase I study was an open-label dose escalation study. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Endpoints included safety, tolerability, preliminary activity, pharmacokinetics and pharmacodynamics.

Results: 31 pts received AUY922 at doses of 8, 16, 22, 28, 40, 54 and 70 mg/m2. Pt characteristics include: median age 60 yrs, 48.4% male, 51.6 % female and WHO performance status 0 (67.7 %) or 1 (32.3 %). Median duration of exposure was 7.3 weeks (range; 0.1, 55.0). The most frequently reported adverse events possibly related to AUY922 were diarrhea-20 pts, (64.5%), night blindness-13 pts, (41.9%), nausea-7 pts (22.6%), fatigue-6 pts (19.4%), rash-6 pts, (19.4%), decreased appetite-5 pts, (16.1%) and vomiting-5 pts (16.1%). Visual symptoms (grade 1–2 and mostly reversible) including night blindness and blurred vision were reported at doses of 22 mg/m2 and higher. A single patient at the 54 mg/m2 dose experienced a dose limiting toxicity of grade 3 fatigue and anorexia. Considering the safety data from a preceding global Phase I study and the potential increase of visual toxicity risk, 70 mg/m2 was declared as the recommended Phase II dose (RPTD) consistent with the RPTD found in the global Phase I study. Stable disease (SD) for at least 8 weeks was reported in 10 pts and 1 rectal carcinoid pt reported a confirmed partial response (PR). Blood concentration of AUY922 reached the peak at the end of infusion and declined slowly with a flat terminal phase.

Conclusions: Weekly IV infusion of single agent AUY922 was well tolerated at the RPTD of 70 mg/m2, confirming the tolerability of the RPTD found in a preceding global Phase I study. Clinical activity was observed in 1 patient in this study, further supporting efficacy of AUY922, as observed in ongoing global clinical studies, and pharmacokinetic parameters were comparable to those observed in non-Japanese patients in the aforementioned global Phase I study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B98.