Pharmacodynamic study of skin biopsy specimens in patients (pts) with refractory or advanced malignancies following administration of AP23573, an mTOR inhibitor

Abstract

3033 Background: The mTOR inhibitor AP23573 is a novel non-prodrug analog of rapamycin. Inhibition of mTOR is marked by a decrease in the phosphorylation of ribosomal protein S6. In a phase I dose-escalation study, pts with advanced solid tumors received AP23573 as a 30-min IV infusion QDx5 every 2 wks. To assess the ability of AP23573 to penetrate tissue and inhibit its intended target, levels of phosphorylated S6 (P-S6) in skin were measured pre and post treatment. Methods: Skin biopsy specimens were collected on Days 1 (pre and 4 h post infusion), 3 (pre) and 15 (pre and 4 h post infusion). Levels of P-S6 (Ser235/236) and p70 S6K, as a control, were evaluated by IHC. The staining intensity (0–3 scale) and the % positive cells were determined and the product of these values used to derive a “staining index” (0–300 range). Results: Thirty-two pts received AP23573 doses ranging from 3 to 28 mg in 6 dose-level cohorts. Skin biopsies were obtained from 28 pts and full analysis has been completed on 23. In 20/23 pts, P-S6 levels were inhibited by >=50% at one or more timepoints after dosing. Staining of total p70 S6K remained constant. On average, the P-S6 staining index was decreased by 27–33% at the 4 h and Day 3 timepoints. In 8/22 pts analyzed, P-S6 inhibition was sustained for at least 10 days post-dosing. The degree of P-S6 inhibition did not appear to correlate tightly with dose, although there was a trend toward lower average post-dose staining indices in the mid- and high-dose groups. Preliminary analysis suggests that inhibition of S6 phosphorylation in skin did not correlate closely with response (PR, MR or SD as determined by RECIST) in this diverse pt population (p=0.19). Conclusions: AP23573 exerted a pharmacodynamic effect in >85% of pts, confirming penetration of the drug in skin as a surrogate for the tumor. These results also support the need for a panel of biomarkers in the tumor as a possible predictor of response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ariad, Immunosignal Transduction, LLC Ariad Ariad Ariad