Background: Aurora Kinase A (AKA) is a key mitotic regulator overexpressed in multiple solid tumors. This open-label dose escalation phase I study evaluated the safety and tolerability of alisertib (MLN8237), an oral AKA inhibitor, in combination with gemcitabine. Methods: Patients (pts) > 18y with refractory solid tumors received 28-day cycles of gemcitabine on days 1, 8, 15 and alisertib twice daily on days 1-3, 8-10, and 15-17. Gemcitabine was given at a standard dose of 1000mg/m². Four dose levels (DL) of alisertib (20-50mg) were planned following a conventional 3+3 design to investigate the occurrence of dose limiting toxicities (DLT) over cycle 1, and to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Anti-tumor activity was assessed by response rate (RECIST 1.1) and progression-free survival. Results: Twenty-one pts were treated with median age 57 y [42-75]; 48% male; PS 0 (7 pts), 1 (13 pts), or 2 (1 pt); median prior therapies was 2 [0-7]; tumor types were NSCLC (7); colorectal (3); poorly differentiated neuroendocrine (3); small cell lung (2); head and neck (2); 1 each of pancreatic, gallbladder, small bowel, and mesothelioma. A median of 4 cycles [1-13] were administered. Two pts experienced DLTs: 1 pt at DL3 had grade 3 urinary tract infection; 1 pt at DL4 developed grade 3 oral mucositis, hyponatremia, and dehydration. The maximum administered dose (DL4) achieved 900 mg alisertib per cycle and was tolerated (1 DLT in 6 pts). Grade 3–4 hematologic toxicities observed included neutropenia (57%), leukopenia (48%), anemia (24%), and thrombocytopenia (14%). Hyponatremia (19%) was the only non-hematologic toxicity observed in > 10% of the pts. Ten of 14 evaluable pts (71%) had stable disease as their best response with remaining 4 pts having disease progression. Conclusions: Alisertib can be safely administered with gemcitabine and the R2PD for alisertib is 50 mg PO BID on days 1-3, 8-10, and 15-17 in combination with full dose gemcitabine. Further clinical evaluation of this combination is warranted and a pre-planned expansion is ongoing in pts with pancreatic adenocarcinoma including evaluation of pharmacokinetic interaction of the combination at the MTD. Clinical trial information: NCT01924260