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A phase I open-label study of the safety, tolerability, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab for relapsed or refractory metastatic colorectal cancer

  • PHASE I STUDIES
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Summary

Background Pazopanib is a multi-targeted tyrosine kinase inhibitor shown to be clinically active in the treatment of various cancer types. This study aimed to evaluate the maximum tolerated regimen (MTR), safety, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab in adult patients with relapsed or refractory metastatic colorectal cancer (mCRC). Patients and methods This was a Phase I, 3 + 3 design, open-label, dose-escalation study (NCT0050943; VEG108925) conducted in sequential cohorts to determine the MTR of pazopanib and irinotecan administered with cetuximab. Twenty-five patients received treatment in three dosing cohorts and were evaluated for safety and tolerability of the combination and pharmacokinetics of individual drugs. Results The MTR was determined to be 400 mg pazopanib per day orally in combination with 150 mg/m2 irinotecan biweekly and 250 mg/m2 cetuximab weekly by infusion. Neutropenia was the main dose-limiting toxicity. Pharmacokinetic results suggested that the overall systemic exposure to SN-38, the active metabolite of irinotecan, was affected by pazopanib to a greater extent than was the systemic exposure to irinotecan itself. Conclusions This study provided evidence for the manageable safety profile and feasibility of using the novel triplet combination of pazopanib, irinotecan, and cetuximab in patients with refractory mCRC. Further large-scale Phase II studies are warranted.

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Acknowledgments

GlaxoSmithKline would like to acknowledge Vina Bachoo and Dr. Mamta Chawla at Kinapse Ltd for their role in the preparation of this manuscript. Editorial assistance was also provided by ProEd Communications, Inc.

Conflict of interest statement

A. B. Suttle, C. Wixon, and C. de Labareyre are employees of GlaxoSmithKline. All other authors have declared no conflicts of interest.

Funding

This study was sponsored by GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania, USA. Editorial support for this report was also funded by GlaxoSmithKline.

Ethical standards

The study was conducted in accordance with the current laws of the country in which it was conducted (France).

Author information

Authors and Affiliations

  1. Institut de Cancérologie de l’Ouest, Nantes, France

    Jaafar Bennouna & Helene Senellart

  2. Medical Oncology Department, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France

    Marion Deslandres & Jean-Pierre Delord

  3. GlaxoSmithKline Research and Development, Marly Le Roi, France

    Cecile de Labareyre

  4. GlaxoSmithKline Research and Development, Stockley Park, UK

    Rodrigo Ruiz-Soto & Claire Wixon

  5. GlaxoSmithKline Research and Development, Upper Providence, USA

    Jeff Botbyl & A. Benjamin Suttle

  6. Institut Claudius Regaud, Département de Médecine, IUCT-Oncopole, 1 Avenue Irene Joliot-Curie, CEDEX 9, 31059, Toulouse, France

    Jean-Pierre Delord

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  1. Jaafar Bennouna
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  2. Marion Deslandres
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Correspondence to Jean-Pierre Delord.

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Bennouna, J., Deslandres, M., Senellart, H. et al. A phase I open-label study of the safety, tolerability, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab for relapsed or refractory metastatic colorectal cancer. Invest New Drugs 33, 138–147 (2015). https://doi.org/10.1007/s10637-014-0142-1

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  • DOI: https://doi.org/10.1007/s10637-014-0142-1

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