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Introduction The Aurora kinases are serine/threonine protein kinases essential for regulation of normal leukotriene receptor agonist mitosis. Aurora kinases A (AAK) and B are overexpressed in hematologic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS); reduction of intracellular AAK results in mitotic inhibition, senescence, and apoptosis in human cell lines . Alisertib (MLN8237) is an investigational, orally available, selective, small-molecule AAK inhibitor  with antitumor activity in preclinical leukemia models [2,3]. Here we report an exploratory phase 2 trial of alisertib in a heterogeneous patient population with AML or high-grade MDS (NCT00830518). The single-agent alisertib regimen administered in this study was determined by prior phase 1 studies [4,5].
Methods In this open-label, phase 2 study, conducted in the USA, Canada, and France, patients received alisertib 50mg BID for 7 days plus 14-days׳ rest in 21-day cycles until disease progression or unacceptable toxicity. Response was evaluated per AML and MDS International Working Group (IWG) criteria [6,7]. Primary endpoint was overall response rate (ORR; CR plus partial response [PR]). ‘CR’ included CR with incomplete blood count recovery (per IWG guidelines) in AML patients and marrow CR in MDS patients; ‘PR’ included incomplete blood count recovery in AML and MDS patients [6,7]. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), and hematologic improvement in MDS patients. The response-evaluable population for the primary endpoint analysis included patients who received ≥1 dose of alisertib and had ≥1 post-baseline response assessment. Safety and tolerability were monitored throughout. Adverse events (AEs) were graded by NCI CTCAE v3.0. The safety population included patients who received ≥1 dose of alisertib. A Simon optimal 2-stage design was used, with 21 patients enrolled in the first stage and ≥2 responses required to proceed to the second stage. Sample size was estimated using a 1-sided test at the significance level of α=0.05, power of 90%, a null hypothesis of response rate ≤5%, and an alternative hypothesis of response rate ≥20%. To obtain 41 response-evaluable patients, enrollment of ~44 patients was projected. Time-to-event data were analyzed by Kaplan–Meier methodology.
Results Fifty-seven patients were enrolled (Table 1). The median number of treatment cycles received was 2 (range 1–26) with similar medians for AML and MDS. The maximum number of cycles received for AML and MDS patients was 26 and 6, respectively, with differences between diseases driven by an increased response rate in AML patients.
Discussion The lack of response in MDS patients compared with AML patients may point to important clues in alisertib clinical mechanism of action. Failure of hematopoeisis in MDS is principally driven by increased apoptosis in the malignant clone, in contrast to marrow suppression by a proliferative clone in AML. In-vitro studies have shown that reduction of intracellular AAK results in mitotic inhibition, senescence, and apoptosis in human cell lines . Thus, alisertib may be unable to stimulate an apoptotic clone in MDS but may suppress a proliferative clone in AML. Transfusion independence was achieved in 13 patients and maintained for 2–5 cycles in 11 patients, suggesting that recovery of normal hematopoiesis can occur. Additional studies are needed to identify predictors of response and to understand how AAK inhibition may induce leukemic cell senescence, a property described with preclinical model systems , which may complement an antimitotic effect. In conclusion, alisertib demonstrated modest single-agent anti-leukemic activity, mostly limited to AML patients in this study. The toxicity profile was generally acceptable, and consistent with expected effects of Aurora kinase inhibition in proliferative tissues [9,10]. To allow for potentially delayed treatment effects by alisertib, improved clinical outcomes in larger populations will likely require additional strategies to enable early disease control. Results of this study of alisertib in AML/MDS highlight the need to develop predictors of response, combination regimens, and other strategies to enhance the clinical utility of treatment with this novel AAK inhibitor.