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

摘要

Aberrant expression of aurora kinase A is implicated in the genesis of variousneoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinaseinhibitor, has demonstrated efficacy as monotherapy in trials of myeloidmalignancy, and this efficacy appears enhanced in combination with conventionalchemotherapies. In this phase I, dose-escalation study, newly diagnosed patientsreceived conventional induction with cytarabine and idarubicin, after whichalisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cyclesof consolidation, incorporating alisertib, and thereafter alisertib maintenancefor up to 12 months. Twenty-two patients were enrolled. One dose limitingtoxicity occurred at dose level 2 (prolonged thrombocytopenia), and therecommended phase 2 dose was established at 30mg twice daily. Commontherapy-related toxicities included cytopenias and mucositis. Only three(14%) patients had persistent disease at mid-cycle, requiring“5+2” reinduction. The composite remission rate (completeremission and complete remission with incomplete neutrophil recovery) was86% (nineteen of twenty-two patients; 90% CI68–96%). Among those over age 65 and those with high-riskdisease (secondary acute leukemia or cytogenetically high-risk disease), thecomposite remission rate was 88% and 100%, respectively. Themedian follow up was 13.5 months. Of those treated at the recommended phase 2dose, the 12-month overall survival and progression-free survival were62% (90% CI 33–81%) and 42% (90%CI 17–65%), respectively. Alisertib is well tolerated whencombined with induction chemotherapy in acute myeloid leukemia, with a promisingsuggestion of efficacy. ( clinicaltrials.gov Identifier:01779843 ).