Phase Ⅱ study of alisertib as a single agent for treating recurrent or progressive atypical teratoid/rhabdoid tumor

摘要

Background. Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options. Methods. We conducted a phase Ⅱ study of Aurora kinase A inhibitor alisertib in patients aged ＜22 years with recurrent AT/RT. Patients received alisertib once daily (80 mg/m~2 as enteric-coated tablets or 60 mg/m~2 as liquid formulation) on Days 1-7 of a 21-day cycle until progressive disease (PD) occurred. Alisertib plasma concentrations were measured in cycle 1 on Days 1 (single dose) and 7 (steady state) and analyzed with noncompartmental phar-macokinetics.Trial efficacy end point was ≥10 participants with stable disease (SD) or better at 12 weeks. Results. SD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0 ± 7.9 at 6 months and 13.3 ± 5.6 at 1 year. One-year overall survival (OS) was 36.7 ± 8.4.Two patients continued treatment for ＞12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77). The 22 patients who received liquid formulation had a higher mean maximum concentration (C_(max)) of 10.1 ± 3.0 μM and faster time to C_(max) (T_(max) = 1.2 ± 0.7 h) than those who received tablets (C_(max) = 5.7 ± 2.4 μM,T_(max) = 3.4 ± 1.4 h). Conclusions. Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.