Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors

Abstract

Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/ MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies.Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n ¼ 12), or days 1, 3, and 5 (schedules B, n ¼ 17, and C, n ¼ 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0.Results: Schedule A MTD was 50 mg/m 2 ; based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m 2 , respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade !3 treatmentrelated serious adverse events reported on schedules B or C.

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

“…On the basis of its promising anticancer efficacy and tolerated toxicity, MLN4924 has undergone preclinical or phase I clinical trials for multiple human malignancies (17)(18)(19). Mechanistically, MLN4924 blocks cullin neddylation, inactivates CRL, induces the accumulation of tumor-suppressive CRL substrates and causes DNA damage, cell cycle arrest, cellular senescence and apoptosis in a tumor cell-specific manner (3,7,15,29,31).…”

“…Previously, MLN4924 exhibited attractive pharmacodynamic effects in phase I studies in patients with advanced solid tumors, relapsed/refractory lymphoma and metastatic melanoma for its tolerable safety profile (17)(18)(19). MLN4924 may function as a novel chemosensitizer or radiosensitizer in multiple types of cancer (20)(21)(22)(23)(24).…”

Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

“…Targeting neddylation pathway has been recently demonstrated as an attractive anticancer strategy, evidenced by the efficacy of the NAE inhibitor MLN4924, a first-in-class anticancer agent, in a multitude of preclinical studies (1)(2)(3)(11)(12)(13)(14)(15)(16)(17)(18)(19). Currently, MLN4924, used as a single agent or in combination with traditional chemotherapeutics, is under investigation in quite a few of phase I/II clinical trials (http://www.clinicaltrials.gov) and has exhibited promising clinical activity in both advanced solid tumors and relapsed/refractory multiple myeloma or lymphoma (18,19).…”

“…Currently, MLN4924, used as a single agent or in combination with traditional chemotherapeutics, is under investigation in quite a few of phase I/II clinical trials (http://www.clinicaltrials.gov) and has exhibited promising clinical activity in both advanced solid tumors and relapsed/refractory multiple myeloma or lymphoma (18,19). Mechanistically, MLN4924 blocks cullin neddylation, inactivates CRL, induces the accumulation of tumor-suppressive CRL substrates, and eventually causes DNA re-replication stress/DNA damage, cell-cycle arrest, senescence, or apoptosis in a cell-type-dependent manner (1-3, 11-14, 20-22).…”

MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

“…Nedd8 serves a role in the activation of the cullin-RING ligases (CRL), also termed SKP1-cullin-F-box (SCF) E3 ligases for its founding member (CRL/SCF) (6), which has been established to be involved in the regulation of multiple DNA replication and repair pathways (7,8). MLN4924 is a recently identified small molecule inhibitor of NAE and is currently in Phase I clinical trials (9,10). By inhibiting neddylation, MLN4924 promotes uncontrolled S-phase DNA replication as well as in the induction of DNA damage and subsequent cell death (11)(12)(13).…”