Purpose: STA-1474 is the prodrug of ganetespib, currently the most advanced Hsp90 inhibitor in human clinical trials. In a Phase I clinical trial, STA-1474 demonstrated biologic activity in dogs with spontaneous tumors. Data from this trial suggested that longer drug infusion times (8 hours versus 1 hour) were potentially associated with greater biologic activity. The purpose of the following study was to extend these observations and identify the optimum dosing schedule of STA-1474 in dogs with spontaneous mast cell tumors (MCT).

Experimental Design: This was a Phase 2 trial in which dogs with spontaneous MCT received STA-1474 (6 mg/kg, per week) under one of four different dosing schedules: once weekly with a 1 hour infusion (cohort A) or 8 hour infusion (cohort B), or twice weekly with a 1 hour infusion given 24 hour (cohort C) or 72 hour (cohort D) between doses. Toxicities, biomarker changes from pre- and two post-treatment biopsies, and tumor responses were assessed.

Results: Twenty-four chemotherapy and radiation naïve dogs with MCT were enrolled. Toxicities were mild and primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Measurable responses were observed from dogs in cohort A (SD=5, PD=1), cohort B (PR=2, SD=4), cohort C (PR=3, SD=3) and cohort D (PR=2, SD=1, PD=1). Biopsies are currently being evaluated by reverse phase protein array and results will be presented.

Conclusions: This study provides further evidence that prolonged exposure to STA-1474 improves biological activity. Dosing STA-1474 on two consecutive days yielded the greatest objective responses (50%) and a disease control rate of 100%. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 synthesis following its inhibition, it is likely that more frequent exposure to ganetespib will demonstrate comparable anti-cancer activity in human patients and is currently being evaluated in a Phase I study.

Citation Format: Cheryl A. London, Misty D. Bear, David A. Proia. The importance of dose schedule with Hsp90 inhibitors: Results from a Phase II study in dogs with mast cell tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3369. doi:10.1158/1538-7445.AM2013-3369

©2013 American Association for Cancer Research
2013