Abstract
SummaryPevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366.
Highlights
Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the neural precursor cellexpressed, developmentally down-regulated 8 (NEDD8)-Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA 02139, USAMedical Center Hungarian Defense Forces, Budapest, Hungary activating enzyme (NAE) [1, 2]
NAE conjugates NEDD8 to cullin-RING ligases (CRLs), which control ubiquitination and proteasomal degradation of substrates involved in cell cycle progression (p21, p27, and cyclin D/E), DNA replication (CDT1), oxidative response (NFR2), and response to hypoxia (HIF1a) [3, 4]
Pevonedistat forms a covalent adduct with NEDD8 that binds tightly to NAE, preventing neddylation; this results in CRL substrate accumulation, which leads to apoptotic cell death [6]
Summary
NAE conjugates NEDD8 to cullin-RING ligases (CRLs), which control ubiquitination and proteasomal degradation of substrates involved in cell cycle progression (p21, p27, and cyclin D/E), DNA replication (CDT1), oxidative response (NFR2), and response to hypoxia (HIF1a) [3, 4]. This conjugation process, called neddylation, activates CRLs to ubiquitinate and degrade their substrates [5]. Pevonedistat forms a covalent adduct with NEDD8 that binds tightly to NAE, preventing neddylation; this results in CRL substrate accumulation, which leads to apoptotic cell death [6]. Dysfunction of the NEDD8 cascade is linked to the pathogenesis of several diseases, including cancer, making it a compelling target for drug development [7, 9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
