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A pharmacodynamically guided dose selection of PF-00337210 in a phase I study in patients with advanced solid tumors

Justine Yang Bruce1, Patricia M LoRusso2, Priscila H Goncalves2

  • 1Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 7105, 1111 Highland Avenue, Madison, WI, 53705, USA. jybruce@medicine.wisc.edu.

Cancer Chemotherapy and Pharmacology
|January 22, 2016
PubMed
Abstract

Insights

PF-00337210, a vascular endothelial growth factor receptor (VEGFR) inhibitor, showed anticancer activity and VEGFR inhibition at well-tolerated doses. The recommended phase 2 dose was determined to be 6 mg twice daily.

Area of Science:

  • Oncology
  • Pharmacology
  • Biomarkers

Background:

  • PF-00337210 is an oral, selective vascular endothelial growth factor receptor (VEGFR) inhibitor.
  • Evaluating biomarkers in real-time aids in determining recommended phase 2 doses (RP2D) and assessing preliminary anticancer activity.

Purpose of the Study:

  • To identify the recommended phase 2 dose (RP2D) of PF-00337210.
  • To evaluate the preliminary anticancer activity of PF-00337210 using a composite biomarker approach.

Main Methods:

  • Patients with advanced cancers received escalating doses of PF-00337210 orally, either once daily (QD) or twice daily (BID).
  • Tumor perfusion and vascularity were assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
  • Blood pressure, soluble VEGFR-2 levels, and hemoglobin levels were monitored to evaluate treatment effects.

Main Results:

  • Forty-six patients were treated; the maximum tolerated dose (MTD) at the QD schedule was 8 mg.
  • Common adverse events included hypertension and fatigue, which were manageable.
  • Vascular response was observed in 10 patients, with 5 out of 6 patients at BID doses showing response. Greatest modulation of soluble VEGFR-2 occurred at 6 mg BID.

Conclusions:

  • PF-00337210 demonstrates significant VEGFR inhibition at well-tolerated doses.
  • Antitumor activity and VEGFR inhibition effects were observed, particularly at BID dosing.
  • The recommended phase 2 dose (RP2D) for PF-00337210 was established as 6 mg BID.
Keywords:
DCEMRI imagingPharmacodynamic analysisTyrosine kinase inhibitorVEGF receptor

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