Integrated Safety Analysis of Single-Agent MLN8237 (alisertib), an Investigational Aurora A Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies and Solid Tumors

Aurora A Kinase (AAK) is a key regulator in the control of mitosis, and amplification/overexpression of AAK has been reported in a wide variety of cancers. MLN8237 (alisertib) is an investigational, oral AAK inhibitor that is being researched in several clinical trials, in a number of different malignancies. Here we report an integrated analysis of the safety profile of single-agent MLN8237.

Single-agent safety data from 8 studies (5 in solid tumors and 3 in hematologic malignancies: C14001–C14007, C14010) were pooled for this analysis, including MLN8237 starting doses above the recommended Phase 3 dose (RP3D) of 50 mg BID × 7 days q 21-days. A data cut-off date of March 29, 2012 was used and includes some ongoing studies.

653 patients were included in this analysis, 490 with solid tumors and 163 with hematologic malignancies. Median age at baseline was 61 years (range 20–88), and 34% and 62%, respectively, had an ECOG performance status of 0 or 1. Patients received a median of 2 cycles of MLN8237 (solid: 2 [range 1–51]; heme: 2 [range 1–34]), and 134 patients (21%) received ≥6 cycles of therapy (solid: n=104 [21%]; heme: n=30 [18%]). In total, 168 patients (26%) had a reduction in MLN8237 dose (solid: n=120 [24%]; heme: n=48 [29%]), including 42 patients (6%) with ≥2 dose reductions (solid: n=32 [7%]; heme: n=10 [6%]). In total, 422 patients received MLN8237 at the RP3D dose of 50 mg BID for 7 days in 21-day cycles. Of these patients, 412 (98%) had an adverse event (AE) of any grade (solid: 295/305 [97%]; heme: 117/117 [100%]), and 328 (78%) had a grade ≥3 AE. Most frequently observed all-cause AEs were fatigue (49%), neutropenia (48%), anemia (45%), and diarrhea (43%). Drug-related AEs were observed in 90% of patients, including at grade ≥3 in 252 (60%; Table). Although the most frequently observed grade ≥3 drug-related AE was neutropenia (37%), only ∼23% of the safety population required G-CSF therapy (cycle 1: n=96), with the greatest use seen in one study of patients with solid tumors (C14007: 38 of 96 patients [40%]). Overall, 24% of patients (solid: 19%; heme: 35%) had drug-related serious AEs, of which the most frequently reported were febrile neutropenia (6%), neutropenia (5%), stomatitis (4%), and anemia (2%). 14% of patients (solid: 10%; heme: 23%) had an AE resulting in treatment discontinuation. In total, 52 (12%) on-study deaths have been recorded (solid: 23 [8%]; heme: 29 [25%]); all were considered as being unrelated to treatment with MLN8237, with the exception of 1 patient with diffuse large B-cell lymphoma who had fatal sepsis.

In patients receiving MLN8237 at the RP3D, AEs were most frequently reported in rapidly proliferating tissues, reflecting the proposed role of MLN8237 in dysregulating mitosis. This is the largest reported safety database with an AAK inhibitor and is consistent with preclinical data demonstrating the Aurora A inhibition of MLN8237. Currently enrolling trials include a phase 3 study to evaluate MLN8237 in patients with relapsed/refractory peripheral T-cell lymphoma.

Benaim:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Off Label Use: Yes – Investigational agent in clinical development for the treatment of advanced hematologic malignancies and solid tumors. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Leonard:Millennium Pharmaceuticals, Inc.: Employment. Freedland:Millennium Pharmaceuticals, Inc.: Employment. Niculescu:Millennium Pharmaceuticals, Inc.: Employment.