Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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).

Schedule ESchedule B
50 mg /m2 (n=16)83 mg/m2 (n=19)≥110 mg/m2 (n=7)
AEs % (all-grade >30% and Gr ≥3 >20%) All Gr ≥3 All Gr ≥3 All Gr ≥3 
Pyrexia 44 68 43 
Dyspnea 38 37 16 43 14 
Diarrhea 38 32 43 
Decreased appetite 38 32 14 
Edema peripheral 38 21 29 
Aspartate aminotransferase increase 31 25 29 
Nausea 31 21 43 
Hypotension 31 13 26 14 14 
Fatigue 31 19 32 16 43 14 
Myalgia 25 32 14 
Febrile neutropenia 19 19 32 26 29 29 
Chills 42 43 
Thrombocytopenia 21 21 14 14 
Sepsis 16 16 14 14 
Schedule ESchedule B
50 mg /m2 (n=16)83 mg/m2 (n=19)≥110 mg/m2 (n=7)
AEs % (all-grade >30% and Gr ≥3 >20%) All Gr ≥3 All Gr ≥3 All Gr ≥3 
Pyrexia 44 68 43 
Dyspnea 38 37 16 43 14 
Diarrhea 38 32 43 
Decreased appetite 38 32 14 
Edema peripheral 38 21 29 
Aspartate aminotransferase increase 31 25 29 
Nausea 31 21 43 
Hypotension 31 13 26 14 14 
Fatigue 31 19 32 16 43 14 
Myalgia 25 32 14 
Febrile neutropenia 19 19 32 26 29 29 
Chills 42 43 
Thrombocytopenia 21 21 14 14 
Sepsis 16 16 14 14 
Disclosures:

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.

Author notes

*

Asterisk with author names denotes non-ASH members.