Phase i Study of the investigational nedd8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with advanced solid tumors

John Sarantopoulos, Geoffrey I. Shapiro, Roger B. Cohen, Jeffrey W. Clark, John S. Kauh, Glen J. Weiss, James M. Cleary, Devalingam Mahalingam, Michael D. Pickard, Héléne M. Faessel, Allison J. Berger, Kristine Burke, George Mulligan, Bruce J. Dezube, R. Donald Harvey

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

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 = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 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/m2; based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m2, 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. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. Conclusions: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with anMTDbetween 50 mg/m2 and 67 mg/m2. DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. Clinical trials are ongoing.

Original languageEnglish (US)
Pages (from-to)847-857
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number4
DOIs
StatePublished - Feb 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Phase i Study of the investigational nedd8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with advanced solid tumors'. Together they form a unique fingerprint.

Cite this