Phase 2 Study of MLN8237, An Investigational Aurora A Kinase (AAK) Inhibitor In Patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndromes (MDS)

AAK is essential for mitotic progression and is amplified or overexpressed in AML and other hematologic malignancies. The investigational agent MLN8237 is an orally available, potent, and selective AAK inhibitor with preclinical activity against leukemias, lymphomas, and myeloma. Phase 1–2 and pharmacodynamic results show a mechanism of selective AAK inhibition, and some durable clinical activity in patients with treatment-resistant malignancies.

Open-label, multicenter, phase 2 trial (NCT00830518) of MLN8237 in patients aged ≥18 years with advanced AML or intermediate-2/high-risk MDS. Eligibility criteria included ECOG performance status 0–2, adequate organ function, and >10% blasts in bone marrow. Patients were not excluded based on number of prior therapies, treatment with hydroxyurea or steroids, prior transplant, or ongoing cytopenias. Patients received 21-day cycles of MLN8237 50 mg BID for 7 days followed by 14 days' rest until disease progression or unacceptable toxicity. The primary endpoint was response rate, defined as complete (CR) plus partial (PR) response, which included CR (CRi) or PR (PRi) with incomplete blood count recovery in AML patients and marrow CR or PRi in MDS patients. Response was evaluated by modified AML/MDS international working group (IWG) criteria; stable disease was defined as failure to achieve PRi but no evidence of progression in AML patients, and as failure to achieve PR but no evidence of progression for >8 weeks in MDS patients. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) version 3.0.

57 patients were enrolled; median age was 72 years (range 46–85), 56% were male, and 81% white. Forty-six (81%) patients had AML, of whom 21 (37%) had secondary leukemia. Of 11 (19%) patients with MDS, 8 had an IPSS score of intermediate-2 (1.5 or 2.0), and 3 had a high (≥2.5) score. Forty-nine (86%) patients had received prior therapies, and 9 (16%) received ≥3 prior therapies. Patients received a median of 2 cycles (range 1–16) of MLN8237. Treatment-related grade 3/4 AEs were seen in 24 (42%) patients and included febrile neutropenia (11%), thrombocytopenia (9%), anemia (9%), fatigue (7%), and neutropenia (7%). Treatment-emergent somnolence was identified in 14 (25%) patients, and grade 3/4 treatment-related somnolence was reported in 2 (4%) patients. Fourteen (25%) patients discontinued due to AEs. Twenty-two on-study deaths were reported, caused by events unrelated to MLN8237, including progressive disease (46%), and sepsis (14%); of these, 9 deaths from AML occurred within 2 months of study entry. Overall, 6 (13%) responses were observed (all AML patients; response-evaluable population n=45); 5 patients had PR. One CR was documented in a 79-year old female with AML and no prior therapy, who presented with 23% bone marrow blasts at the time of progression from MDS/RAEB-2, and remains in CR through 16 cycles (1 year). Seventeen (49%) AML and 2 MDS (20%) patients achieved stable disease. Ongoing analyses suggest that co-morbidities influenced clinical outcomes.

Data suggest that single-agent MLN8237 has anti-leukemia activity with a 13% response rate (all AML) in this clinical study of patients with advanced, mainly pre-treated disease. In patients with rapidly progressive disease, these results indicate that improved outcomes require strategies to enhance both disease control and risk management in early cycles, allowing time needed to achieve clinical benefit from AAK inhibition. These results support further clinical studies of MLN8237 in heme-lymphatic malignancies and solid tumors.

Goldberg: Millennium Pharmaceuticals, Inc.: Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of AML/MDS. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; GSK Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees. Gyan:Amgen: Research Funding; Janssen-Cilag: Research Funding; Celegene: Honoraria, Research Funding; Roche: Honoraria. Schiller:Millennium Pharmaceuticals, Inc.: Research Funding. Jung: Millennium Pharmaceuticals, Inc.: Employment. Leonard:Millennium Pharmaceuticals, Inc.: Employment. Fingert:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Westervelt:Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau.