Background: About 13,000 cases of soft tissue and bone sarcoma are diagnosed annually in the US. Despite surgery many patients (pts) develop recurrent disease. Response rates (RR) to chemotherapy are low; new agents are needed. In gene array studies Aurora Kinase A (AURKA) is commonly overexpressed. Inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel, oral, ATP-competitive, selective small-molecule inhibitor of AURKA. Methods: This multi-center phase II study of alisertib in pts with advanced/metastatic sarcoma was conducted through the Alliance for Clinical Trials in Oncology (A091102). Adequate performance status, organ function, and measurable disease (RECIST v1.1) were required. Pts enrolled into histology-defined cohorts: 1) liposarcoma (LPS), 2) leiomyosarcoma (LMS), 3) undifferentiated sarcoma (US), 4) malignant peripheral nerve sheath tumor (MPNST), or 5) other. Alisertib 50mg PO BID d1-d7 was given every 21 days until progressive disease (PD) or unacceptable toxicity. The primary endpoint was confirmed RR in each of 5 cohorts. Progression-free survival (PFS) was a secondary endpoint. 1 confirmed response in the first 9 pts expanded enrollment in a cohort to 24 using a Simon 2-stage design. Results: 72 pts were enrolled at 24 sites (12 LPS, 10 LMS, 13 US, 10 MPNST, and 27 Other). Median age was 55 (range 20-84); 54% were male; 58/38/4% were ECOG PS 0/1/2. 1 confirmed PR in the Other cohort (angiosarcoma) expanded to 2nd stage accrual. The histology-specific cohorts ceased at the 1st stage. Overall, 76% have PD; 25% have died, with median follow-up of 4.4 months (0.4-11.9). 12-week PFS was 73% (LPS), 44% (LMS), 23% (US), 57% (MPNST), and 39% (Other). Common grade 3-4 adverse events included (%): mucositis (13), anemia (14), leukopenia (22), and neutropenia (40). Conclusions: Alisertib was well-tolerated in this study of multiple sarcoma histologic subtypes. Rare responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR endpoint, PFS was promising. Alisertib warrants further study in sarcoma. Clinicaltrials.gov:NCT01653028. Funded by the Alliance for Clinical Trials in Oncology Clinical trial information: NCT01653028.