Background: AAK is a serine/threonine kinase that regulates the G2-M transition and centrosome separation during mitosis. Alisertib (MLN8237) is an oral AAK inhibitor active in aggressive lymphoma, with 4 of 8 T cell lymphoma pts responding in a phase II trial (Friedberg JCO 2013). This phase II study was conducted to further investigate the efficacy of alisertib in PTCL. Methods: Eligible pts with histologically confirmed relapsed/refractory PTCL had normal organ function, ANC ≥1500/mm³ and platelets ≥75,000/mm³. Pts received alisertib 50mg BID for 7d on 21d cycles. Tumors were evaluated for expression levels of AAK, ABK, Myc, Bcl2, PI3Kδ, and Notch1 and quantified by image analysis. Results: Of 42 pts accrued, 37 eligible pts had a median age of 62 (range 22-86). Histologies included PTCL not otherwise specified (NOS)(13), angioimmunoblastic (AITL)(9), transformed mycosis fungoides (MF) (7), adult T-cell lymphoma (ATLL) (4), anaplastic large cell (ALCL) (2) and extranodal NK/T-cell (NK/T) (2). With a median number of 3 (range 1-18) prior therapies, 3 pts had undergone a prior stem cell transplant and 20 were refractory to prior therapy. Grade 3 and 4 AEs in ≥ 5% of pts included neutropenia (30%), anemia (27%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%) and rash (5%). 6 pts discontinued therapy and 9 were dose reduced due to AEs. Treatment was discontinued most commonly for PTCL progression. 2 complete responses and 7 partial responses were observed for a response rate (ORR) of 24% (95%CI: 12-41%). Among the most common subtypes, (PTCL NOS, AITL and ALCL), the ORR was 33% (95%CI: 16-55%). Of 27 pts with available biopsies, 0 and 6 expressed AAK and ABK respectively. Conclusions: Alisertib has antitumor activity in PTCL, including heavily pretreated pts. Toxicities to date were manageable and reversible. An international randomized phase III trial is comparing alisertib to investigator’s choice in PTCL. Support: NIH/NCI Cooperative Group Grants CA32102 and CA38926; CA21115; CA21946; and Takeda Pharmaceuticals. Clinical trial information: NCT01466881.