Abstract
SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017
Highlights
NEDD8, a ubiquitin-like small protein, has been identified as a regulator of the activity of a group of E3 enzymes within the ubiquitin-proteasome system, including the cullin-RING E3 ubiquitin ligases (CRLs), which control the turnover of several proteins involved in cancer biology [7, 8]
Patients were to have ≥1 measurable or non-measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [16], an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function
All enrolled patients FAS Patients excluded from FAS All treated patients Untreated patients dose-limiting toxicities (DLTs)-evaluable patients DLT-unevaluable patients PK-evaluable patients PK-unevaluable patients Pharmacodynamic-evaluable patients Pharmacodynamic-unevaluable patients PGx-evaluable patients PGx-unevaluable patients
Summary
NAE is an essential protein in the NEDD8 conjugation (neddylation) pathway, affecting cancer cell growth and survival through activation of CRLs [8]. This elucidation of the cellular role of NAE in cancer pathogenesis has led to the consideration of NAE as a potential therapeutic target in various malignancies, resulting in the instigation of several early phase clinical studies with the NAE inhibitor MLN4924 (pevonedistat) in both hematologic and solid tumor types [9,10,11,12]
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