title: Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma.
abstract: OBJECTIVE
  Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma.
  
  
  METHODS
  Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles.
  
  
  RESULTS
  Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease.
  
  
  CONCLUSIONS
  Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.
authors.affiliation: Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. jjshah@mdanderson.org.
authors.forename: Jatin J
authors.initials: JJ
authors.lastname: Shah
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Jakubowiak
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
authors.affiliation: Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lebovic
authors.affiliation: New York University School of Medicine, NYU Perlmutter Cancer Center, New York, New York.
authors.forename: Catherine
authors.initials: C
authors.lastname: Diefenbach
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kelly
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, Massachusetts.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Hua
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, Massachusetts.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Berger
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, Massachusetts.
authors.forename: George
authors.initials: G
authors.lastname: Mulligan
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, Massachusetts.
authors.forename: Hélène M
authors.initials: HM
authors.lastname: Faessel
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, Massachusetts.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tirrell
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, Massachusetts.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Dezube
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D000075687:NEDD8 Protein; D009364:Neoplasm Recurrence, Local; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D019233:Retreatment; D016896:Treatment Outcome; D014452:Ubiquitins / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; C539933:pevonedistat