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A two-part Phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics

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Abstract

Background

Cediranib (RECENTIN™) is an oral, highly potent VEGF inhibitor. This study evaluated the effect of food on the pharmacokinetics of cediranib and compared the administration of continual cediranib via two dosing strategies using this as a platform to investigate pharmacodynamic imaging biomarkers.

Methods

Sixty patients were randomised to receive two single doses of cediranib in either fed/fasted or fasted/fed state (Part A). In continual dosage phase (Part B), patients were randomised to a fixed-dose or dose-escalation arm. Exploratory pharmacodynamic assessments were performed using DCE-MRI and CT enhancing fraction (EnF).

Results

In part A, plasma AUC and C max of cediranib were lower in the presence of food by a mean of 24 and 33%, respectively (94% CI: AUC, 12–34% and C max, 20–43%), indicating food reduces cediranib plasma exposure. In part B, cediranib 30 mg/day appeared to be the most sustainable for chronic dosing. Continuous cediranib therapy was associated with sustained antivascular effects up to 16 weeks, with significant reductions in DCE-MRI parameters and CT EnF.

Conclusions

It is recommended that cediranib be administered at least 1 h before or 2 h after food. Evidence of antitumour activity was observed, with significant sustained effects upon imaging vascular parameters.

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References

  1. Wedge SR, Kendrew J, Hennequin LF et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400

    Article  PubMed  CAS  Google Scholar 

  2. Batchelor TT, Sorensen AG, di Tomaso E et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95

    Article  PubMed  CAS  Google Scholar 

  3. Drevs J, Siegert P, Medinger M et al (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:3045–3054

    Article  PubMed  CAS  Google Scholar 

  4. Mulders P, Hawkins R, Nathan P, de Jong I, Mookerjee B, Osanto S, Pike L, Porfiri E, Protheroe A, Gore ME (2008) Cediranib (RECENTIN™) in patients with advanced renal cell carcinoma: results of a randomized Phase II study. In: 7th International kidney cancer symposium, Edition

  5. Matulonis U, Berlin S, Krasner C, Tyburski K, Lee J, Roche M, Ivy P, Penson R (2007) Phase II study of Cediranib (RECENTIN™, AZD2171) in recurrent epithelial ovarian cancer. Mol Cancer Ther 6:abst 263

    Google Scholar 

  6. Sridhar SS, Mackenzie MJ, Hotte SJ et al. (2008) Activity of cediranib (AZD2171) in patients (pts) with previously untreated metastatic renal cell cancer (RCC). A phase II trial of the PMH Consortium. J Clin Oncol (Meeting Abstracts) 26:261s, abstr 5047

  7. Laurie SA, Gauthier I, Arnold A et al (2008) Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 26:1871–1878

    Article  PubMed  CAS  Google Scholar 

  8. Shields A, Heath E, DeLuca P, Pilat M, Wozniak A, Gadgeel S, Puchalski T, Xu J, Liu Q, LoRusso P (2007) AZD2171 in combination with various anticancer regimens: follow-up results of a phase I multi-cohort study. J Clin Oncol 25 (18S):abst 3544

    Google Scholar 

  9. O’Connor JP, Jackson A, Parker GJ, Jayson GC (2007) DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer 96:189–195

    Article  PubMed  Google Scholar 

  10. Morgan B, Thomas AL, Drevs J et al (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 21:3955–3964

    Article  PubMed  CAS  Google Scholar 

  11. Liu G, Rugo HS, Wilding G et al (2005) Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol 23:5464–5473

    Article  PubMed  CAS  Google Scholar 

  12. O’Connor JP, Jayson GC, Jackson A et al (2007) Enhancing fraction predicts clinical outcome following first-line chemotherapy in patients with epithelial ovarian carcinoma. Clin Cancer Res 13:6130–6135

    Article  PubMed  Google Scholar 

  13. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  14. Ton NC, Parker GJ, Jackson A et al (2007) Phase I evaluation of CDP791, a PEGylated di-Fab’ conjugate that binds vascular endothelial growth factor receptor 2. Clin Cancer Res 13:7113–7118

    Article  PubMed  CAS  Google Scholar 

  15. Mullamitha SA, Ton NC, Parker GJ et al (2007) Phase I evaluation of a fully human anti-alpha v integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res 13:2128–2135

    Article  PubMed  CAS  Google Scholar 

  16. O’Connor JPB, Carano RAD, Clamp AR et al (2009) Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging. Clin Cancer Res 15:6674–6682

    Article  PubMed  Google Scholar 

  17. Tofts PS (1997) Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging 7:91–101

    Article  PubMed  CAS  Google Scholar 

  18. Parker G, Jackson A, Waterton JC, Buckley DL Automated Arterial Input Function Extraction for T1-Weighted DCE-MRI. In: Proceedings International Soc. Mag. Reson. Med. Edition, abst 1264

  19. Parker GJ, Roberts C, Macdonald A et al (2006) Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI. Magn Reson Med 56:993–1000

    Article  PubMed  Google Scholar 

  20. Evelhoch JL (1999) Key factors in the acquisition of contrast kinetic data for oncology. J Magn Reson Imaging 10:254–259

    Article  PubMed  CAS  Google Scholar 

  21. Rorden C, Brett M (2000) Stereotaxic display of brain lesions. Behav Neurol 12:191–200

    PubMed  Google Scholar 

  22. Rugo HS, Herbst RS, Liu G et al (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23:5474–5483

    Article  PubMed  CAS  Google Scholar 

  23. Batchelor T, Duda DG, di Tomaso E, Kozak K, Zhang W-T, Ancukiewicz M, Loeffler JS, Wen P, Sorensen G, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. In: Proceedings Am. Assoc. Cancer Res. 48, Edition

  24. Trarbach T, Drevs J, Strumberg D, Gauler TC, Schneider V, Eberhardt WE, Marotti M, Puchalski TA, Swaisland AJ (2008) A phase I, open-label, multicenter study of cediranib and AZD0530 in patients with advanced solid tumors. J Clin Oncol 26(15S):175S (abst 3592)

    Google Scholar 

  25. Langenberg M, van Herpen CM, de Bono JS, Unger C, Schellens JH, Hoekman K, Blum HE, Le Maulf F, Fielding A, Voest EE (2008) Optimal management of emergent hypertension during treatment with a VEGF signaling inhibitor: a randomized phase II study of cediranib. J Clin Oncol 26:abst 3555

    Google Scholar 

Download references

Acknowledgments

We would like to thank the patients who entered this study and all the research teams at all the sites. In addition, we would like to thank CRUK for their support for the clinical research teams involved within this study. We thank Dr Jen Lewis, from Mudskipper Bioscience, who provided medical-writing support funded by AstraZeneca.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK

    Claire L. Mitchell, J. P. B. O’Connor & G. C. Jayson

  2. Imaging Science and Biomedical Engineering, School of Cancer and Imaging Sciences, The University of Manchester, Manchester, M13 9PT, UK

    J. P. B. O’Connor, C. Roberts, Y. Watson, A. Jackson, S. Cheung & G. J. M. Parker

  3. The University of Manchester Biomedical Imaging Institute, The University of Manchester, Manchester, M13 9PT, UK

    J. P. B. O’Connor, C. Roberts, Y. Watson, A. Jackson, S. Cheung, G. J. M. Parker & G. C. Jayson

  4. Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN, UK

    J. Evans & C. Kelly

  5. King’s College London, Guy’s Hospital, London, SE1 9RT, UK

    J. Spicer & S. Rudman

  6. CRUK Medical Oncology Unit, The Churchill Hospital, Oxford, OX3 7LJ, UK

    A. Harris & M. Middleton

  7. AstraZeneca, Alderley Park, Macclesfield, SK10 4TF, UK

    A. Fielding, J. Tessier & H. Young

Authors
  1. Claire L. Mitchell
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  2. J. P. B. O’Connor
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  3. C. Roberts
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  4. Y. Watson
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  5. A. Jackson
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  6. S. Cheung
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  7. J. Evans
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  8. J. Spicer
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  9. A. Harris
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  10. C. Kelly
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  11. S. Rudman
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  12. M. Middleton
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  13. A. Fielding
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  14. J. Tessier
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  15. H. Young
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  16. G. J. M. Parker
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  17. G. C. Jayson
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Corresponding author

Correspondence to Claire L. Mitchell.

Additional information

RECENTIN™ is a trade mark of the AstraZeneca group of companies.

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Mitchell, C.L., O’Connor, J.P.B., Roberts, C. et al. A two-part Phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics. Cancer Chemother Pharmacol 68, 631–641 (2011). https://doi.org/10.1007/s00280-010-1534-3

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  • DOI: https://doi.org/10.1007/s00280-010-1534-3

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