MLN4924, a Novel Investigational Inhibitor Of NEDD8-Activating Enzyme (NAE), In Adult Patients With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS): Results From Multiple Dosing Schedules In a Phase 1 Study
NEDD8-activating enzyme (NAE) regulates the NEDD8 conjugation pathway, and is required for activity of the cullin-RING E3 ligases (CRLs). CRLs control proteasomal degradation of several substrates involved in cell-cycle regulation, signal transduction, DNA replication and stress response including proteins important for survival of AML cells. MLN4924, a first-in-class NAE inhibitor, has shown antitumor activity in preclinical AML models. This study evaluated safety and tolerability of MLN4924 given on multiple dosing schedules. A maximum tolerated dose (MTD) of 59 mg/m2 given on days 1, 3 and 5 of a 21-day cycle (schedule A) was previously reported (Erba et al, EHA 2011); complete responses were observed in 4/27 patients for this schedule (most common AE: diarrhea [44%], most common Gr ≥3 AE: febrile neutropenia [33%]). Here we report on two additional schedules.
Adults with AML or MDS and good performance status received MLN4924 as a 60-min IV infusion on one of two schedules for up to 1 year or until disease progression. Schedule B patients received escalating doses of MLN4924 on days 1, 4, 8 and 11 every 21 days. Schedule E patients received a fixed dose of MLN4924 on days 1, 3 and 5 every 21 days. Adverse events (AEs) and responses were graded according to published guidelines. Serial blood samples were obtained during cycle 1 for pharmacokinetic (PK) and pharmacodynamic analyses.
On schedule B: 26 patients were enrolled (77% male), median age was 70.5 yrs, 23 had AML and 3 had MDS (2 had advanced disease with marrow blasts exceeding 10%). Patients received MLN4924 at 83 (n=19), 110 (n=4), and 147 mg/m2 (n=3). On Schedule E: 16 patients (69% male) received 50 mg/m2 MLN4924, median age was 70.5 yrs, 14 AML and 2 MDS (1 with advanced disease). Three patients on schedule B had dose-limiting toxicities (DLTs): 1 patient at 110 mg/m2; orthostatic hypotension (Gr 3); 2 patients at 147 mg/m2; cardiac failure (Gr 4; n=1), fatal lactic acidosis, hypotension, gastrointestinal necrosis, acute renal failure and myocardial ischemia (each Gr 4; n=1). On schedule E, 2 patients had DLTs: morbilliform rash (Gr 3; n=1); and increased aspartate/alanine aminotransferases (Gr 2/3; n=1). Most common all-grade and Gr ≥3 AEs are shown in the table. The MTD for Schedule B was determined as 83 mg/m2. On schedules B/E, 3/2 patients received ≥4 cycles, 0/4 remain on treatment; discontinuations were due to progressive disease (11/10), AEs (8/0), and other reasons (7/2) respectively. In 17 patients treated at 83 mg/m2 on schedule B and 16 patients on schedule E, individual PK profiles showed a biphasic disposition phase following completion of the first infusion. MLN4924 plasma concentrations were detectable 24–48 hours (schedule B) and 24 hours (schedule E) post dosing. Schedule B geometric mean (%CV) Cmax was 1255 ng/mL (25.1%), AUC24hr was 3936 ng•h/mL (22.6%); schedule E values were Cmax of 669 ng/mL (24.4%) and AUC24hr of 2614 ng•h/mL (21.4%). Observed increases in mean Cmax and AUC24hr were dose-proportional between 50 and 83 mg/m2 after single dosing. Pharmacodynamic data demonstrated evidence of target and pathway inhibition for all patients on both schedules. On schedule B, of 20 response-evaluable patients (18 AML, 2 MDS), 2 (11%) AML patients had partial responses (PR), 13 (72%) had stable disease. On schedule E, of 12 response-evaluable patients (11 AML, 1 MDS), 1 (8%) AML patient had a PR, 7 (59%) maintained stable disease and the MDS patient (8%) had a response.
Both schedules appeared to be generally well tolerated and NAE inhibition with MLN4924 resulted in clinical activity in highly refractory/multiply relapsed patients. Based on safety and observed clinical activity across schedules, the recommended phase 2 dose for single agent MLN4924 in AML/MDS is 50 mg/m2 given on days 1, 3 and 5 of a 21-day cycle. A study of MLN4924 with azacitidine in treatment-naïve AML patients older than 60 years is ongoing (NCT01814826).
Off Label Use: Investigational agent MLN4924 for the treatment of patients with AML and high-grade or low-grade MDS. Hua:Millennium: The Takeda Oncology Company: Employment. Blakemore:Millennium: The Takeda Oncology Company: Employment. Faessel:Millennium: The Takeda Oncology Company: Employment. Dezube:Millennium: The Takeda Oncology Company: Employment. Medeiros:Millennium: The Takeda Oncology Company: Research Funding.
DeAngelo, DJ; Erba, HP; Maris, MB; Swords, RT; Anwer, F; Altman, JK; Hua, Z; Blakemore, SJ; Faessel, H; Dezube, BJ; Medeiros, BC
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