title: Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors.
abstract: OBJECTIVE
  To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule.
  
  
  METHODS
  Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m(2) were explored.
  
  
  RESULTS
  Forty patients [24M/16F, median age 61 years (45-79)] were enrolled. At 4.5 mg/m(2), dose-limiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m(2), DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m(2), one patient experienced reversible grade 4 blurred vision. The maximum tolerated dose (MTD) is 4.0 mg/m(2). No complete or partial responses during treatment were observed; one patient at 4.0 mg/m(2) had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination half-life of 5.3 to 15.1 hours. Overall drug exposure increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15- to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10- to 25-fold increase.
  
  
  CONCLUSIONS
  The MTD for E7107 using this schedule is 4.0 mg/m(2). Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107.
authors: Authors' Affiliations: Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain; Eisai Inc., Woodcliff Lake, New Jersey; Eisai Inc., Tsukuba, Japan; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Ferry A L M
authors: FA
authors: Eskens
authors: Francisco J
authors: FJ
authors: Ramos
authors: Herman
authors: H
authors: Burger
authors: James P
authors: JP
authors: O'Brien
authors: Adelaida
authors: A
authors: Piera
authors: Maja J A
authors: MJ
authors: de Jonge
authors: Yoshiharu
authors: Y
authors: Mizui
authors: Erik A C
authors: EA
authors: Wiemer
authors: Maria Josepa
authors: MJ
authors: Carreras
authors: José
authors: J
authors: Baselga
authors: Josep
authors: J
authors: Tabernero
mesh_terms: D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D004334:Drug Administration Schedule; D004852:Epoxy Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D018942:Macrolides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012333:RNA, Messenger / Q000096:biosynthesis; D017381:Spliceosomes / Q000187:drug effects* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; C557411:E 7107; D004852:Epoxy Compounds; D018942:Macrolides; D012333:RNA, Messenger