Justine Yang Bruce1, Patricia M LoRusso2, Priscila H Goncalves2, Elisabeth I Heath2, Elizabeth Sadowski3, David R Shalinsky4, Yanwei Zhang5, Anne M Traynor6, Aurora Breazna7, Alejandro D Ricart8, Michael Tortorici9, Glenn Liu10. 1. Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 7105, 1111 Highland Avenue, Madison, WI, 53705, USA. jybruce@medicine.wisc.edu. 2. Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI, 48201, USA. 3. E3/366 Clinical Science Center, Department of Radiology, University of Wisconsin SMPH, 600 Highland Avenue, Madison, WI, 53792-3252, USA. 4. Department of Pharmacology, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA. 5. Department of Statistics, Pfizer Inc., 610 Main Street, Cambridge, MA, 02139, USA. 6. Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 3103, 1111 Highland Avenue, Madison, WI, 53705, USA. 7. Department of Biostatistics, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA. 8. Department of Biotechnology and Oncology Research, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA. 9. Department of Clinical Pharmacology, Pfizer, Inc., 235 E. 42nd Street, New York, NY, 10017, USA. 10. Wisconsin Institute for Medical Research, University of Wisconsin Carbone Cancer Center, Room 7105, 1111 Highland Avenue, Madison, WI, 53705, USA.
Abstract
PURPOSE: 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 AND 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.
PURPOSE: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 AND 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.
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