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Phase I and pharmacokinetic study of dasatinib and cetuximab in patients with advanced solid malignancies

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Summary

Background Combined inhibition of epidermal growth factor receptor (EGFR) and Src family kinases (SFK) may lead to improved therapeutic effects. We evaluated the combination of dasatinib, an inhibitor of SFK and other kinases, and cetuximab, an anti-EGFR monoclonal antibody. Patients and methods Patients with advanced solid malignancies received cetuximab intravenously on a standard weekly schedule and dasatinib orally, once daily at 3 dose levels: (1) 100 mg, (2) 150 mg, (3) 200 mg. Pharmacokinetic and pharmacodynamic studies of dasatinib were performed prior to starting cetuximab and following 14 days of treatment. Results Twenty-five patients (3 dose level 1; 19 dose level 2; 3 dose level 3) were initially treated. Three patients developed dose-limiting toxicities: 1 at dose level 2 (headache) and 2 at dose level 3 (headache, nausea). Grade 3–4 toxicities in more than 2 patients included: dyspnea (4), vomiting (4), nausea (3), hypersensitivity reactions (3), headache (3) and anemia (3). Twenty-one patients developed headache (8 grade 1; 10 grade 2), which occurred after the loading of cetuximab and lasted 1–3 days. Six additional patients were treated with dasatinib starting 3 days after the loading dose of cetuximab; none developed headache after dasatinib. Dasatinib pharmacokinetics and a transient decrease in SFK PY416 levels in peripheral blood mononuclear cells were not altered by cetuximab. Patients with higher plasma TGF-alpha levels had worse progression-free survival. Conclusions Dasatinib 150 mg once daily plus weekly cetuximab is recommended for phase II studies. Early-onset headache was ameliorated by starting dasatinib after cetuximab.

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Funding

Supported in part by Bristol-Myers Squibb, and the Head and Neck SPORE Grant No. P50 CA097190-06 from the National Cancer Institute

Role of funding sources

BMS provided drug and support for the study costs and pharmacokinetics; the Head and Neck Cancer SPORE provided support for the conduct of the correlative studies.

Conflict of interest statement

Drs. Argiris, Grandis and Egloff have received research funding from BMS

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Athanassios Argiris, Trevor M. Feinstein, Leonard J. Appleman & Ronald G. Stoller

  2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Lin Wang

  3. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Tianbing Yang, Jennifer R. Grandis & Ann Marie Egloff

  4. Bristol-Myers Squibb, New York City, NY, USA

    Shruti Agrawal

  5. Division of Hematology/Oncology, UT Health Science Center at San Antonio Cancer Therapy & Research Center, 7979 Wurzbach Road MC8232 Zeller Building- 4th Floor, Room Z418, San Antonio, TX, 78229, USA

    Athanassios Argiris

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  1. Athanassios Argiris
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  2. Trevor M. Feinstein
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  3. Lin Wang
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  7. Ronald G. Stoller
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  8. Jennifer R. Grandis
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  9. Ann Marie Egloff
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Correspondence to Athanassios Argiris.

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Argiris, A., Feinstein, T.M., Wang, L. et al. Phase I and pharmacokinetic study of dasatinib and cetuximab in patients with advanced solid malignancies. Invest New Drugs 30, 1575–1584 (2012). https://doi.org/10.1007/s10637-011-9732-3

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  • DOI: https://doi.org/10.1007/s10637-011-9732-3

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