A Phase I Study of the Aurora a Kinase Inhibitor Alisertib in Combination with 7+3 Induction Chemotherapy in Patients with Acute Myeloid Leukemia
Authors: Fathi Amir T. , Wander Seth A. , Blonquist Traci M. , Ballen Karen K. , Attar Eyal C. , McAfee Steven L. , Chen Yi-Bin , Graubert Timothy A. , Brunner Andrew M. , Joseph Christelle , Perry Ashley M. , Burke Meghan , Silver Regina , Ramos Aura Y. , Connolly Christine , Neuberg Donna S. , Amrein Philip C. 
Published: October 2019

Abstract
The aurora kinases play an essential role in regulating mitosis and cell division. Over-expression of aurora kinases A and B has been associated with poor-risk features in acute myeloid leukemia (AML). Preclinical studies suggest that small molecule aurora kinase inhibitors have activity in AML cell lines. Alisertib (MLN8237), a novel Aurora-A kinase inhibitor, has been generally well tolerated in early clinical trials of hematological malignancies, including AML. This study sought to evaluate tolerability of alisertib combined with standard “7+3” induction chemotherapy for AML.
In this phase I, 3+3 cohort dose-escalation study, alisertib was administered with standard 7+3 induction for newly diagnosed AML. Those with acute promyelocytic leukemia or with AML and core-binding factor alterations were excluded. All patients received 7+3 induction (continuous infusion cytarabine 200mg/m2 x 7 days and intravenous idarubicin 12mg/m2 x 3 days), after which on day 8, alisertib was administered twice daily (BID) for 7 days. Dose escalation occurred via three cohorts (10mg BID, 20mg BID, 30mg BID). All underwent a mid-induction bone marrow biopsy, following the course of alisertib, to assess for residual disease, which if present, was to be treated with 5+2 re-induction (cytarabine 200mg/m2 x 5 days, idarubicin 12mg/m2 x 2 days) without alisertib. Following induction, up to four cycles of consolidation were allowed, using cytarabine (3g/m2 BID days 1,3,5 for those aged <60 and 2g/m2 daily days 1-5 for those aged ≥60) followed by alisertib, according to dose cohort, on days 6-12. After consolidation, alisertib maintenance was initiated, at cohort dose level, for days 1-7 of 21 day cycles, to be continued for 12 months or until disease progression. Those eligible for stem cell transplant (SCT), following induction and/or consolidation courses, were removed from study for this purpose.
Currently, 14 patients are enrolled on study (n=3, 10mg BID; n=7, 20mg BID; n=4, 30mg BID). The median age was 62 (range 43-75); 9 (64%) were male, and all but 3 were Caucasian. One patient (7%) had therapy-related AML and six (43%) had underlying myelodysplasia. FLT3 mutations were detected in 3 (21%), NPM1 mutations in 2 (14%), CEBPA mutations in 2 (14%), and IDH1/IDH2 mutations in 4 patients (28.4%). One patient in cohort 2 died of sepsis, deemed unrelated to study drug, prior to completion of the toxicity assessment period and was replaced. Five patients have gone on to SCT. All patients received induction, 7 patients have undergone first consolidation, 3 a second consolidation, 2 a third consolidation, 1 a fourth consolidation, and 1 patient has started maintenance therapy. Alisertib has been well tolerated. All patients have experienced expected grade 4 toxicities of anemia, thrombocytopenia, and febrile neutropenia seen during the induction phase of treatment. At initial dose of 10mg BID, no dose-limited toxicities (DLTs) were encountered. In the 20mg BID cohort, one DLT was encountered, of delayed thrombocytopenia (G4 at day 40). The final cohort, at 30mg BID, is currently accruing (4 of 6 enrolled). No other DLTs have been detected, and other toxicities on study will be presented. The maximum tolerated dose (MTD) will be established upon completion of this cohort. To date, 11 of 12 (92%) evaluable patients have achieved remission following induction (8 cases of CR and 3 of CRp). During the course of the study, one patient has experienced relapse, and none have died. Thirteen of 14 evaluable patients had an ablated mid-induction marrow biopsy, with the remaining patient showing 6% blasts in a 20% cellular marrow at mid-induction. None of the patients have undergone re-induction with 5+2 at mid-induction. We anticipate that the study will be fully enrolled and closed to further accrual by the time of presentation.
Alisertib, a novel aurora A kinase inhibitor, appears to be well tolerated in conjunction with standard induction chemotherapy in newly diagnosed AML. Currently, 13 of 14 treated patients have demonstrated marrow ablation at the mid-induction point of therapy, and none have required re-induction with 5+2. Eleven of 12 evaluable patients have achieved remission following induction. These results suggest that alisertib is well-tolerated and may hold promise as a therapeutic agent in AML, when combined with induction chemotherapy. Ongoing efforts seek to define the MTD and establish appropriate dosing for phase II studies.

Disclosures
Fathi: Millennium: Research Funding; Seattle Genetics: Advisory Board, Advisory Board Other; Agios: Advisory Board, Advisory Board Other. Attar:Agios: Employment.