Phase II Clinical Trial of Alisertib, an Aurora a Kinase Inhibitor, in Combination with Induction Chemotherapy in High-Risk, Untreated Patients with Acute Myeloid Leukemia
Authors: Brunner Andrew M. , Blonquist Traci M. , DeAngelo Daniel J. , McMasters Malgorzata , Winer Eric S. , Hobbs Gabriela S. , Amrein Philip C. , Hock Hanno , Steensma David P. , Garcia Jacqueline S. , Luskin Marlise R. , Stone Richard M. , Ballen Karen K. , Rosenblatt Jacalyn , Avigan David E. , McAfee Steven L , Moran Jenna A. , Bergeron Meghan , Foster Julia , Bertoli Christina , McGregor Kristin , Fishman Kaitlyn , Macrae Molly , Burke Meghan , Behnan Tanya T. , Som Tina T. , Ramos Aura Y. , Vartanian Megan K. , Nelson Nicole , Logan Emma , Lombardi Story Jennifer , Connolly Christine , Neuberg Donna S , Chen Yi-Bin , Graubert Timothy A. , Fathi Amir T. 
Published: October 2019

Abstract

Background: Aurora kinases play essential roles in regulating cell division, and increased expression has been noted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We previously conducted a phase I study of alisertib combined with "7+3" induction chemotherapy in untreated patients with AML, and found the combination to have an adverse event profile similar to 7+3 alone, with promising efficacy, particularly for patients with high-risk disease, such as those who were older, with high-risk molecular features, or with secondary AML. These patients collectively have a historically grim prognosis, with an approximate rate of remission, in trials, of 45%. CPX-351, a liposomal daunorubicin-cytarabine product, was recently approved for use in secondary AML after it was demonstrated to be superior to 7+3 induction, with a median survival of 9.6 months versus 5.9 months among older patients, in a phase 3 trial. We recently completed accrual to a phase II study of alisertib plus induction chemotherapy in patients with untreated, high-risk AML.
Methods: Patients were eligible if they had AML defined by WHO 2016 and either an adverse-risk karyotype (European Leukemia Net Guidelines), secondary (post-MDS/MPN) AML, therapy-related AML, or age ≥ 65 vears. We used a Simon two-stage design, assuming a null composite remission rate (complete remission [CR] and CR with incomplete count recovery [CRi]) of 45%. Patients could be enrolled prior to cytogenetic classification, but those without adverse-risk karyotype who lacked other eligibility criteria were removed before day 8 and replaced. All patients received continuous infusion cytarabine 100mg/m2 on days 1-7 [D1-7] and idarubicin 12mg/m2 [or daunorubicin 60mg/m2] D1-3 (7+3). On D8 through D15, alisertib at 30mg BID orally (PO) was administered. All underwent a mid-induction marrow biopsy to assess for residual disease, which if present, was treated with 5+2 re-induction without alisertib. Following remission, patients could receive up to 4 consolidation cycles with cytarabine (3g/m2 BID D1,3,5 for age <60 and 2g/m2 daily D1-5 for age ≥60) with alisertib PO at 30mg BID, D6-12, and alisertib maintenance at 30mg BID PO (D1-7 of 3 week cycles) thereafter for 12 months. Patients who pursued stem cell transplant (SCT) were followed for EFS and OS.
Results: 39 eligible patients were enrolled. The median age was 67 (range 33-83); 25 (64%) were male, and 33 (85%) were Caucasian. 22 patients (56%) had secondary AML (16 with antecedent MDS, 2 with antecedent CMML, 1 with antecedent MPN, and 3 with therapy-related AML). 13 (33%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (18%), NPM1 in 7 (18%), IDH1 in 5 (13%), IDH2 in 5 (13%), CEBPA in 3 (8%), and TP53 mutations in 4 (10%) patients. 33 patients (85%) demonstrated an ablated marrow at mid-treatment, and six (15%) received re-induction at mid-treatment. 8 patients (21%) were refractory to induction, and five (13%) died prior to response assessment due to infection or bleeding. The 30-day and 60-day mortality rates were 8% and 13%, respectively. Patients experienced expected grade 4 toxicities of leukopenia, anemia, thrombocytopenia, and febrile neutropenia; no new attributable safety signals were detected. The CR+CRi rate was 64% (2-stage 95% CI 48-79%) with 20 patients (51%) achieving CR and 5 (13%) achieving Cri. The CR+CRi rate was 59% (13 of 22) in those with secondary AML, 67% (18 of 27) in those aged ≥ 65, 77% (10 of 13) in those with adverse risk karyotype, and 75% (3 of 4 patients) in patients with TP53 mutations. One (3%) patient achieved a partial remission. Based on the composite remission rate of 64%, the combination was deemed effective per study design. 5 patients have relapsed to date. 10 have received at least 1 cycle of consolidation, 16 patients (41%) have gone on to SCT. With a median follow-up of 14 months (Figure), the 12-month overall survival (OS) is 51% (37-65%). Although the data continues to mature, median OS is 12.2 months (90% CI 8.8-NA). In the subset of patients achieving a CR+CRi, the 12-month relapse-free survival was 52% (90% CI 34-67%).
Conclusions: Alisertib, a novel aurora A kinase inhibitor, combined with conventional induction, is efficacious and demonstrates a promising rate of remission and survival among patients with previously untreated high-risk AML. Larger randomized studies are under consideration to better assess the promise of this novel combination.
Figure. Figure.

Disclosures
Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. DeAngelo:Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; Amgen: Consultancy; Takeda: Honoraria; Blueprint Medicines: Honoraria, Research Funding. Amrein:Takeda: Research Funding. Steensma:Acceleron: Consultancy; Amphivena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; H3 Biosciences: Research Funding; Janssen: Consultancy, Research Funding; Kura: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Otsuka: Membership on an entity's Board of Directors or advisory committees; Syros: Research Funding; Takeda: Consultancy. Garcia:Celgene: Consultancy. Rosenblatt:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria.