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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib

Authors: Noriyuki Koyama, Kenichi Saito, Yuki Nishioka, Wataru Yusa, Noboru Yamamoto, Yasuhide Yamada, Hiroshi Nokihara, Fumiaki Koizumi, Kazuto Nishio, Tomohide Tamura

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.

Methods

Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients by twice-daily dosing in 3-week cycles; 2 weeks of treatment followed by 1 week of rest until discontinuation. Blood samples for plasma proteins were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. Selected clinical outcomes, including tumor shrinkage and adverse events (AEs), were used for correlative analyses of pharmacokinetic parameters and PD biomarkers.

Results

Tumor shrinkage and changes in PD biomarkers (increased vascular endothelial growth factor [VEGF] and stromal cell-derived factor 1 alpha [SDF1α] levels and decreased soluble VEGF receptor 2 [sVEGFR2] levels) significantly correlated with increasing lenvatinib exposure. Observed changes in levels of VEGF, SDF1α, and sVEGFR2 were maintained on day 15 of cycle 1, but returned to baseline during the 1-week rest period, and similar changes were induced by reinstitution of treatment in cycle 2. The worst grades of hypertension, proteinuria, and fatigue were associated with changes in VEGF and HGF at day 8 of cycle 1. Maximum tumor shrinkage was correlated with increased SDF1α levels. Decreased sVEGFR2 level was also correlated with tumor shrinkage and frequency of hypertension, proteinuria, and fatigue. Tumor shrinkage significantly correlated with the worst grade of proteinuria, but not with hypertension or fatigue.

Conclusion

PD biomarker changes observed in plasma angiogenic proteins are correlated with lenvatinib-induced tumor shrinkage and AEs. Our findings warrant further assessment of plasma proteins associated with angiogenesis as potential biomarkers of lenvatinib activity.

Trial registration

ClinicalTrial.gov: NCT00280397 (January 20, 2006).
Appendix
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Metadata
Title
Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib
Authors
Noriyuki Koyama
Kenichi Saito
Yuki Nishioka
Wataru Yusa
Noboru Yamamoto
Yasuhide Yamada
Hiroshi Nokihara
Fumiaki Koizumi
Kazuto Nishio
Tomohide Tamura
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-530

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