title: Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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/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 treatment-related 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 an MTD between 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, Texas. Sarantopoulo@uthscsa.edu.
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.affiliation: Early Drug Development Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.affiliation: Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: John S
authors.initials: JS
authors.lastname: Kauh
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, Arizona.
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.affiliation: Early Drug Development Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Pickard
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Hélène M
authors.initials: HM
authors.lastname: Faessel
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Berger
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Kristine
authors.initials: K
authors.lastname: Burke
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: George
authors.initials: G
authors.lastname: Mulligan
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Dezube
authors.affiliation: Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D003517:Cyclopentanes / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use* / Q000633:toxicity; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D011743:Pyrimidines; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat