title: A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma.
abstract: Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles. Results 26 patients received pevonedistat 50-278 mg/m(2) on schedule A; 11 patients received pevonedistat 157 mg/m(2) on schedule B. The schedule A MTD was 209 mg/m(2): dose-limiting toxicities (DLTs) included grade 3 hypophosphatemia and grade 3 increased blood creatinine (associated with grade 3 hyperbilirubinemia). Two schedule A patients experienced acute organ failure toxicities, one of whom experienced grade 5 acute renal failure. Dose escalation did not occur in schedule B: DLTs included grade 3 myocarditis, grade 2 acute renal failure, and grade 2 hyperbilirubinemia in a single patient. Pevonedistat pharmacokinetics were approximately dose-proportional across the dose range studied, with a biphasic disposition profile characterized by a short elimination half-life (~10 h). Pharmacodynamic studies showed increases in NAE-regulated transcripts post-treatment; all post-dose biopsy samples were positive for pevonedistat-NEDD8 adduct. One schedule A patient achieved a partial response; 15 patients had stable disease (4 lasting ≥6.5 months). Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue.
authors.affiliation: Department of Medicine/Medical Oncology, University of Washington Medical Center/Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, 825 Eastlake Ave W, G4-830, Seattle, WA, 98109-1023, USA. sbhatia@uw.edu.
authors.forename: Shailender
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Departments of Medicine (Perlmutter Cancer Center) and Dermatology, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.affiliation: The Angeles Clinic and Research Institute, Translational Research & Cutaneous Oncology, Los Angeles, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Boasberg
authors.affiliation: Department of Medicine/Medical Oncology, University of Washington Medical Center/Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, 825 Eastlake Ave W, G4-830, Seattle, WA, 98109-1023, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Thompson
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Mulligan
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Pickard
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Hélène
authors.initials: H
authors.lastname: Faessel
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Dezube
authors.affiliation: The Angeles Clinic and Research Institute, Translational Research & Cutaneous Oncology, Los Angeles, CA, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
mesh_terms: D000328:Adult; D000368:Aged; D003517:Cyclopentanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D003517:Cyclopentanes; D011743:Pyrimidines; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat
keywords: Melanoma; NAE inhibition; Nrf-2; Pevonedistat; Phase I