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

Cancer Chemotherapy and Pharmacology
Justine Yang BruceGlenn Liu

Abstract

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. 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. 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 ...Continue Reading

References

Feb 7, 2001·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M S GordonD Adelman
Jun 1, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·David H JohnsonFairooz Kabbinavar
Jun 4, 2004·The New England Journal of Medicine·Herbert HurwitzFairooz Kabbinavar
Dec 23, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Dirk StrumbergSiegfried Seeber
May 4, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Anne L ThomasWilliam P Steward
May 21, 2005·Annals of Oncology : Official Journal of the European Society for Medical Oncology·S N HoldenH I Hurwitz
Jul 20, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Hope S RugoGeorge Wilding
Nov 30, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sandrine FaivreEric Raymond
Dec 15, 2006·The New England Journal of Medicine·Alan SandlerDavid H Johnson
Jan 12, 2007·The New England Journal of Medicine·Robert J MotzerRobert A Figlin
Jun 15, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Lee S RosenRoy S Herbst
Nov 17, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Mark J Ratain, Robert H Glassman
Nov 17, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bernardo H L GoulartBruce A Chabner
May 9, 2008·The New England Journal of Medicine·Robert S Kerbel
Jun 11, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Herbert I HurwitzLini Pandite
Nov 18, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Glenwood D GossLesley Seymour
Dec 2, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Afshin Dowlati
Dec 2, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·A Craig LockhartWilliam P Tew
Dec 24, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Klaus MrossRolf Kaiser
Mar 10, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Giorgio ScagliottiNasser Hanna
Jul 8, 2010·Annals of Oncology : Official Journal of the European Society for Medical Oncology·W FiedlerE Boven
Dec 7, 2010·Annals of Oncology : Official Journal of the European Society for Medical Oncology·D J JonkerS Galbraith
Mar 30, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sophie Postel-VinayXavier Paoletti
Apr 6, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Eric Van CutsemEdward Lin
Apr 6, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Alberto F Sobrero, Paolo Bruzzi
Apr 30, 2011·Journal of the National Cancer Institute·Brian I RiniRobert J Motzer
Feb 15, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jonas BerghCarla Giorgetti

❮ Previous
Next ❯

Citations

May 15, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Mohammad M Al-SaneaWagdy M Eldehna

❮ Previous
Next ❯

Related Concepts

Related Feeds

Arterial-Venous in Development & Disease

Arterial-venous development may play a crucial role in cardiovascular diseases. Here is the latest research.