title: Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma.
abstract: OBJECTIVE
  Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker.
  
  
  METHODS
  Patients were randomly assigned to placebo or 200 or 400 mg twice per day of sorafenib. DCE-MRI was performed at baseline and 4 weeks. DCE-MRI parameters, area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC(90)), and volume transfer constant of contrast agent (K(trans)) were calculated for a metastatic site selected in a blinded manner. Primary end point was change in K(trans).
  
  
  RESULTS
  Of the 56 assessable patients, 48 underwent two MRIs; 44 MRIs were assessable for study end points. Mean K(trans) log ratios were 0.131 (standard deviation [SD], 0.315), -0.148 (SD, 0.382), -0.271 (SD, 0.499) in placebo, 200- and 400-mg cohorts, respectively (P = .0077 for trend) corresponding to changes of +14%, -14%, and -24%. IAUC(90) log ratios were 0.041 (SD, 0.197), -0.040 (SD, 0.132), -0.356 (SD, 0.411), respectively (P = .0003 for trend), corresponding to changes of +4%, -4%, and -30%. Using a log-rank test, IAUC(90) and K(trans) changes were not associated with progression-free survival (PFS). Patients with high baseline K(trans) had a better PFS (P = .027).
  
  
  CONCLUSIONS
  IAUC(90) and K(trans) are pharmacodynamic biomarkers for sorafenib, but variability is high and magnitude of effect is less than previously reported. Changes in DCE-MRI parameters after 4 weeks of sorafenib are not predictive of PFS, suggesting that these biomarkers are not surrogate end points. The value of baseline K(trans) as a prognostic or predictive biomarker requires additional study.
authors.affiliation: University of Chicago, Chicago, IL 60637, USA.
authors.forename: Olwen M
authors.initials: OM
authors.lastname: Hahn
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.forename: Milica
authors.initials: M
authors.lastname: Medved
authors.forename: Gregory
authors.initials: G
authors.lastname: Karczmar
authors.forename: Emily
authors.initials: E
authors.lastname: Kistner
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Manchen
authors.forename: Myrosia
authors.initials: M
authors.lastname: Mitchell
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D003287:Contrast Media; D004311:Double-Blind Method; D005260:Female; D019786:Gadolinium DTPA; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010919:Placebos; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077157:Sorafenib; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D003287:Contrast Media; D010671:Phenylurea Compounds; D010919:Placebos; D011725:Pyridines; D009536:Niacinamide; C064925:gadodiamide; D000077157:Sorafenib; D019786:Gadolinium DTPA