Dataset Information

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

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.

SUBMITTER: Bruce JY

PROVIDER: S-EPMC6849384 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Bruce Justine Yang JY LoRusso Patricia M PM Goncalves Priscila H PH Heath Elisabeth I EI Sadowski Elizabeth E Shalinsky David R DR Zhang Yanwei Y Traynor Anne M AM Breazna Aurora A Ricart Alejandro D AD Tortorici Michael M Liu Glenn G

Cancer chemotherapy and pharmacology 20160120 3

<h4>Purpose</h4>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.<h4>Patients and methods</h4>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 ...[more]

PMID: 26791870

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Dataset Information

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

Purpose

Patients and methods

Results

Conclusions

Publications

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

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