title: Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib.
abstract: BACKGROUND
  Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.
  
  
  METHODS
  Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients by twice-daily dosing in 3-week cycles; 2 weeks of treatment followed by 1 week of rest until discontinuation. Blood samples for plasma proteins were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. Selected clinical outcomes, including tumor shrinkage and adverse events (AEs), were used for correlative analyses of pharmacokinetic parameters and PD biomarkers.
  
  
  RESULTS
  Tumor shrinkage and changes in PD biomarkers (increased vascular endothelial growth factor [VEGF] and stromal cell-derived factor 1 alpha [SDF1α] levels and decreased soluble VEGF receptor 2 [sVEGFR2] levels) significantly correlated with increasing lenvatinib exposure. Observed changes in levels of VEGF, SDF1α, and sVEGFR2 were maintained on day 15 of cycle 1, but returned to baseline during the 1-week rest period, and similar changes were induced by reinstitution of treatment in cycle 2. The worst grades of hypertension, proteinuria, and fatigue were associated with changes in VEGF and HGF at day 8 of cycle 1. Maximum tumor shrinkage was correlated with increased SDF1α levels. Decreased sVEGFR2 level was also correlated with tumor shrinkage and frequency of hypertension, proteinuria, and fatigue. Tumor shrinkage significantly correlated with the worst grade of proteinuria, but not with hypertension or fatigue.
  
  
  CONCLUSIONS
  PD biomarker changes observed in plasma angiogenic proteins are correlated with lenvatinib-induced tumor shrinkage and AEs. Our findings warrant further assessment of plasma proteins associated with angiogenesis as potential biomarkers of lenvatinib activity.
  
  
  BACKGROUND
  ClinicalTrial.gov: NCT00280397 (January 20, 2006).
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koyama
authors.forename: Kenichi
authors.initials: K
authors.lastname: Saito
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishioka
authors.forename: Wataru
authors.initials: W
authors.lastname: Yusa
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. ttamura@ncc.go.jp.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D042501:Angiogenic Proteins / Q000097:blood*; D054316:Biomarkers, Pharmacological / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism; D018450:Disease Progression; D004334:Drug Administration Schedule; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D042501:Angiogenic Proteins; D054316:Biomarkers, Pharmacological; D001798:Blood Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C531958:lenvatinib