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Phase I open-label study of cediranib, an oral inhibitor of VEGF signalling, in combination with the oral Src inhibitor saracatinib in patients with advanced solid tumours

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Summary

Combining different targeted anticancer agents may improve clinical outcomes. This Phase I study investigated cediranib, an oral inhibitor of vascular endothelial growth factor signalling in combination with saracatinib, an oral Src inhibitor. The primary endpoint was safety/tolerability. Secondary assessments included pharmacokinetics and preliminary efficacy. Patients and Methods Patients with advanced solid tumours received cediranib 20, 30 or 45 mg/day for 7 days followed by daily treatment with cediranib at the same dose plus saracatinib 175 mg/day. Results Thirty-nine patients received cediranib (20 mg, n = 6; 30 mg, n = 6; 45 mg, n = 27 [n = 20 in cohort expansion]) plus saracatinib. In the cediranib 45 mg cohort, 59% of patients required dose reduction/pause compared with 33% in each of the other two cohorts. There was one dose-limiting toxicity (hypertension; 45 mg cohort). The most common adverse events were hypertension (67%), diarrhoea (62%), dysphonia (46%) and fatigue (39%). There was no evidence of a clinically significant effect of saracatinib on cediranib pharmacokinetics and vice versa. 22/35 evaluable patients had a best response of stable disease. Conclusions All cediranib doses were tolerated; however, in patients with advanced solid tumours, for combination with saracatinib 175 mg/day, cediranib 20 or 30 mg/day was more sustainable than 45 mg/day.

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Acknowledgements

We thank Dr Helen Jones, from Mudskipper Bioscience, who provided writing support funded by AstraZeneca. This study was supported by funding from AstraZeneca.

Conflicts of interest

W.E.E.E has received lecturer fees and compensation as an advisory role (AstraZeneca, Roche, GSK, Novartis, Pfizer, Sanofi-aventis, Bayer Schering, Boehringer Ingelheim, Bristol Myers, OSI, Merck Serono, Amgen). S.LS., M.M. and K.H.B. are employees of AstraZeneca. T.T., B.S., T.C.G., V.S., D.S. and J.D. have no conflict of interest to declare.

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Authors and Affiliations

  1. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisbug-Essen Essen, Hufelandstr. 55, 45122, Essen, Germany

    Tanja Trarbach, Thomas C. Gauler & Wilfried E. E. Eberhardt

  2. Marienhospital Herne, Herne, Germany

    Beate Schultheis & Dirk Strumberg

  3. Cancer Hospital SanaFontis, Freiburg, Germany

    Vesile Schneider & Joachim Drevs

  4. AstraZeneca, Alderley Park, Macclesfield, UK

    Stephanie Le Scouiller, Marcelo Marotti & Kathryn H. Brown

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  1. Tanja Trarbach
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Trarbach, T., Schultheis, B., Gauler, T.C. et al. Phase I open-label study of cediranib, an oral inhibitor of VEGF signalling, in combination with the oral Src inhibitor saracatinib in patients with advanced solid tumours. Invest New Drugs 30, 1962–1971 (2012). https://doi.org/10.1007/s10637-011-9754-x

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