Phase II study of alisertib as a single agent in recurrent or progressive atypical teratoid rhabdoid tumors.

Abstract

10542 Background: We conducted a Phase II study of alisertib, small-molecule inhibitor of Aurora A kinase, as single-agent treatment in patients < 22 y with recurrent or progressive atypical teratoid rhabdoid tumors (ATRT) (NCT02114229). Methods: Patients received alisertib once daily [80 mg/m2 (enteric-coated tablets) or 60 mg/m2 (liquid)] on Days 1–7 of a 21-day cycle for 2 y or until progressive disease (PD). Therapy was considered promising if ≥10 patients were without PD by MR imaging at 12 wk. Molecular groups were determined using Infinium Methylation EPIC BeadChips and the Heidelberg classifier. Alisertib plasma concentrations were measured in cycle 1, on Days 1 (single dose) and 7 (steady state) and analyzed using population-based modeling. Results: Data from 30 patients representing all 3 molecular groups [SHH (10/26), MYC (10/26), TYR (6/26), unknown (4/26)] was analyzed. One patient remains on therapy. The study did not meet the efficacy end point as only 8/29 patients were without PD after 12 wk, including 1 with partial response. Progression-free survival (PFS) was 31%±8.2% at 6 months and 15.8%±6.5% at 1 y. One- year overall survival (OS) was 42.1%±9.2%. One patient remained on treatment for > 12 months, and another for > 18 months. The median treatment duration was 44 days (range, 2–653 days). There was no difference in OS (p = 0.096) or PFS (p = 0.98) by molecular groups. Neutropenia was the most common adverse effect (77%). After single-dose alisertib, we observed higher mean maximum concentration (Cmax) 10.1±3.0 µM and faster time to Cmax (Tmax = 1.2±0.7 h) in the 22 patients who received liquid formulation than those who received tablets (Cmax = 5.7±2.4 µM, Tmax = 3.4±1.4 h). Drug exposure did not differ between the formulations (AUC0-∞ = 58.6±25 h·µM). Average apparent oral clearance was 2.32 L/h per m2, which was about half that reported in adults. Serial CSF samples were collected in 2 patients; the CSF/plasma AUC ratios were 1.2%-2.7%. Conclusions: Although the study did not meet the efficacy end point, alisertib was well tolerated as a single agent in children with recurrent ATRT. A third of the patients demonstrated disease stabilization for > 6 months. Treatment response beyond 1 y was seen in 2 patients Clinical trial information: NCT02114229.