title: A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer.
abstract: OBJECTIVE
  The antisense oligonucleotide LY2275796 blocks expression of cap-binding protein eukaryotic initiation factor 4E (eIF-4E), an mRNA translation regulator upregulated in tumors. This phase I study sought an appropriate LY2275796 dose in patients with advanced tumors.
  
  
  METHODS
  A 3-day loading dose, then weekly maintenance doses, were given to 1 to 3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations and tumor biopsies to quantify eIF-4E mRNA/protein.
  
  
  RESULTS
  Thirty patients with stage 4 disease received 1 or more LY2275796 dose. A dose-limiting toxicity was observed at 1,200 mg, with 1,000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1 to 2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and postdose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and 7 patients achieved stable disease (minimum of 6 weeks) as best response, with 2 patients on therapy for more than 3 months (one with melanoma, one with cystadenocarcinoma of the head/neck).
  
  
  CONCLUSIONS
  LY2275796 was well tolerated up to 1,000 mg. Because tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.
authors.affiliation: Clinical Center for Targeted Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. dshong@mdanderson.org
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Yun
authors.initials: Y
authors.lastname: Oh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wheler
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Les
authors.initials: L
authors.lastname: Brail
authors.forename: Sophie
authors.initials: S
authors.lastname: Callies
authors.forename: Valérie
authors.initials: V
authors.lastname: André
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Kadam
authors.forename: Aejaz
authors.initials: A
authors.lastname: Nasir
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Holzer
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.forename: Mayer
authors.initials: M
authors.lastname: Fishman
authors.forename: George
authors.initials: G
authors.lastname: Simon
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000187:drug effects*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000627:therapeutic use*; D014157:Transcription Factors / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; C569652:LY 2275796; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors