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An apparent clinical pharmacokinetic drug–drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism

Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug–drug interaction observed when RO5323441 was administered in combination with bevacizumab.

Methods

The four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4). A two-compartment linear population PK model was developed from these four studies to characterize the PK of RO5323441 in patients with cancer.

Results

The PK properties of RO5323441 were similar in the first three studies. However, substantially higher RO5323441 exposures were observed in Study 4 when RO5323441 was administered in combination with bevacizumab. A linear two-compartmental population PK model indicated that the co-administration of bevacizumab would decrease the clearance of RO5323441 by 53%. Clinical data suggested that the decrease in RO5323441 clearance was inversely associated with bevacizumab exposure.

Conclusions

The exact reason for the increase in RO5323441 exposure following bevacizumab co-administration is not currently known. One possibility is a drug–drug interaction via a target-trapping mechanism that is mediated by the vascular endothelial growth factor receptor-1 (VEGFR-1).

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Acknowledgements

The authors would like to thank the patients and their families for their participation in this study, and the staff at the study sites, in particular the Department of Neurology, University Hospital of Zürich, Zürich, Switzerland; Department of Oncology, Rigshospitalet, Copenhagen, Denmark; Division of Medical Oncology, National Cancer Center, Singapore; National University Cancer Institute, Singapore; Neuro-oncologie, Hôpital de la Timone, Marseille, France; Clinical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom. Support for third-party writing assistance for this article, furnished by Mike Parsons, PhD and Jamie Ashman, PhD, was provided by Prism Ideas.

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Correspondence to Ka Wang.

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All of the authors are employees of Roche.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the studies.

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Wang, K., Stark, F.S., Schlothauer, T. et al. An apparent clinical pharmacokinetic drug–drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism. Cancer Chemother Pharmacol 79, 661–671 (2017). https://doi.org/10.1007/s00280-017-3242-8

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  • DOI: https://doi.org/10.1007/s00280-017-3242-8

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