Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).