title: A pharmacodynamically guided dose selection of PF-00337210 in a phase I study in patients with advanced solid tumors.
abstract: OBJECTIVE
  PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210.
  
  
  METHODS
  Patients (Pts) with advanced cancers were treated once (QD) or twice daily (BID) with escalating doses. Acute effects on tumor perfusion and vascularity were assessed using DCE-MRI, weekly BP readings, soluble VEGFR-2, and hemoglobin levels.
  
  
  RESULTS
  Forty-six pts were treated with 0.67-9 mg QD and 4-6 mg BID of PF-00337210. Nineteen pts (41%) previously received VEGF/VEGFR inhibitors. Two pts had dose-limiting toxicity (DLT) at 9 mg QD (troponin I increase and hypertension). The MTD at QD dose was 8 mg. Common drug-related adverse events were hypertension, fatigue, proteinuria, and nausea. Hypertension incidence and intensity corresponded with dose, but was well controlled with medication. Two confirmed partial responses and minor regressions (>10 to <30% reduction in target lesions) were noted. Complete DCE-MRI was acquired in 21 pts (20 evaluable for vascular response). Ten pts were vascular responders, including 5/6 pts at BID doses. Greatest modulation of soluble VEGFR-2 was at 6 mg BID. The maximum change from baseline in diastolic BP was higher at BID doses. There were no significant differences for systolic BP and hemoglobin levels.
  
  
  CONCLUSIONS
  PF-00337210 has profound VEGFR inhibition effects at well-tolerated doses. Antitumor activity and VEGF inhibition effects were observed across BID doses. The RP2D was 6 mg BID.
authors.affiliation: Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 7105, 1111 Highland Avenue, Madison, WI, 53705, USA. jybruce@medicine.wisc.edu.
authors.forename: Justine Yang
authors.initials: JY
authors.lastname: Bruce
authors.affiliation: Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI, 48201, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI, 48201, USA.
authors.forename: Priscila H
authors.initials: PH
authors.lastname: Goncalves
authors.affiliation: Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI, 48201, USA.
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Heath
authors.affiliation: E3/366 Clinical Science Center, Department of Radiology, University of Wisconsin SMPH, 600 Highland Avenue, Madison, WI, 53792-3252, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sadowski
authors.affiliation: Department of Pharmacology, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Shalinsky
authors.affiliation: Department of Statistics, Pfizer Inc., 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 3103, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Traynor
authors.affiliation: Department of Biostatistics, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA.
authors.forename: Aurora
authors.initials: A
authors.lastname: Breazna
authors.affiliation: Department of Biotechnology and Oncology Research, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA.
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Ricart
authors.affiliation: Department of Clinical Pharmacology, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tortorici
authors.affiliation: Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 7105, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D054316:Biomarkers, Pharmacological; C562231:PF 00337210; D011804:Quinolines; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: DCEMRI imaging; Pharmacodynamic analysis; Tyrosine kinase inhibitor; VEGF receptor