title: Serum C-Telopeptide Collagen Crosslinks and Plasma Soluble VEGFR2 as Pharmacodynamic Biomarkers in a Trial of Sequentially Administered Sunitinib and Cilengitide.
abstract: OBJECTIVE
  Fit-for-purpose pharmacodynamic biomarkers could expedite development of combination antiangiogenic regimens. Plasma sVEGFR2 concentrations ([sVEGFR2]) mark sunitinib effects on the systemic vasculature. We hypothesized that cilengitide would impair microvasculature recovery during sunitinib withdrawal and could be detected through changes in [sVEGFR2].
  
  
  METHODS
  Advanced solid tumor patients received 50 mg sunitinib daily for 14 days. For the next 14 days, patients were randomized to arm A (cilengitide 2,000 mg administered intravenously twice weekly) or arm B (no treatment). The primary endpoint was change in [sVEGFR2] between days 14 and 28. A candidate pharmacodynamic biomarker of cilengitide inhibition of integrin αvβ3, serum c-telopeptide collagen crosslinks (CTx), was also measured.
  
  
  RESULTS
  Of 21 patients, 14 (7 per arm) received all treatments without interruption and had all blood samples available for analysis. The mean change and SD of [sVEGFR2] for all sunitinib-treated patients was consistent with previous data. There was no significant difference in the mean change in [sVEGFR2] from days 14 to 28 between the arms [arm A: 2.8 ng/mL; 95% confidence interval (CI), 2.1-3.6 vs. arm B: 2.0 ng/mL; 95% CI, 0.72-3.4; P = 0.22, 2-sample t test]. Additional analyses suggested (i) prior bevacizumab therapy to be associated with unusually low baseline [sVEGFR2] and (ii) sunitinib causes measurable changes in CTx.
  
  
  CONCLUSIONS
  Cilengitide had no measurable effects on any circulating biomarkers. Sunitinib caused measurable declines in serum CTx. The properties of [sVEGFR2] and CTx observed in this study inform the design of future combination antiangiogenic therapy trials.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Peter H
authors.initials: PH
authors.lastname: O'Donnell
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Sanja
authors.initials: S
authors.lastname: Karovic
authors.affiliation: Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois. Department of Health Studies, The University of Chicago, Chicago, Illinois.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Karrison
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Linda
authors.initials: L
authors.lastname: Janisch
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Levine
authors.affiliation: Cancer Therapy Evaluation Program of the National Cancer Institute, Bethesda, Maryland.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Harris
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Blase N
authors.initials: BN
authors.lastname: Polite
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois. mmaitlan@medicine.bsd.uchicago.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000097:blood* / Q000493:pharmacokinetics; D024042:Collagen Type I / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000097:blood* / Q000493:pharmacokinetics; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics; D012910:Snake Venoms / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood* / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D024042:Collagen Type I; D007211:Indoles; D010455:Peptides; D011758:Pyrroles; D012910:Snake Venoms; C052929:collagen type I trimeric cross-linked peptide; C422910:Cilengitide; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib