title: Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies.
abstract: OBJECTIVE
  Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies.
  
  
  METHODS
  Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m(2) starting dose was doubled (one patient/dose) until 1.0 mg/m(2) based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response.
  
  
  RESULTS
  Ixazomib was escalated from 0.125 to 2.34 mg/m(2) to determine the MTD (n = 23); patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m(2): grade 3 pruritic rash; 2.34 mg/m(2): grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m(2). Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal half-life was 3.8-7.2 days; plasma exposures increased dose-proportionally and drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement.
  
  
  CONCLUSIONS
  In patients with solid tumors, ixazomib was associated with a manageable safety profile, limited antitumor activity, and evidence of downstream proteasome inhibition effects.
authors.affiliation: University of Michigan Comprehensive Cancer Center, 7302 CC SPC 5948, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5948, USA, dcsmith@umich.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
authors.forename: Thea
authors.initials: T
authors.lastname: Kalebic
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Daniel
authors.initials: D
authors.lastname: Sullivan
authors.forename: Gordana
authors.initials: G
authors.lastname: Vlahovic
authors.forename: John S
authors.initials: JS
authors.lastname: Kauh
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Berger
authors.forename: Stephen
authors.initials: S
authors.lastname: Tirrell
authors.forename: Neeraj
authors.initials: N
authors.lastname: Gupta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Bacco
authors.forename: Deborah
authors.initials: D
authors.lastname: Berg
authors.forename: Guohui
authors.initials: G
authors.lastname: Liu
authors.forename: Jianchang
authors.initials: J
authors.lastname: Lin
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Hui
authors.forename: John A
authors.initials: JA
authors.lastname: Thompson
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000328:Adult; D000368:Aged; D001896:Boron Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019337:Hematologic Neoplasms / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D051700:Activating Transcription Factor 3; D001896:Boron Compounds; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine