Investigational New Drugs

, Volume 30, Issue 4, pp 1575–1584 | Cite as

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

  • Athanassios Argiris
  • Trevor M. Feinstein
  • Lin Wang
  • Tianbing Yang
  • Shruti Agrawal
  • Leonard J. Appleman
  • Ronald G. Stoller
  • Jennifer R. Grandis
  • Ann Marie Egloff
PHASE I STUDIES

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.

Keywords

Dasatinib Cetuximab Src Epidermal growth factor receptor Phase I Pharmacokinetic Pharmacodynamic 

Notes

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

Supplementary material

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Figure S1 (PPT 136 kb)
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Figure S2 (PPT 135 kb)
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ESM 1 (XLS 34 kb)

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Athanassios Argiris
    • 1
    • 5
  • Trevor M. Feinstein
    • 1
  • Lin Wang
    • 2
  • Tianbing Yang
    • 3
  • Shruti Agrawal
    • 4
  • Leonard J. Appleman
    • 1
  • Ronald G. Stoller
    • 1
  • Jennifer R. Grandis
    • 3
  • Ann Marie Egloff
    • 3
  1. 1.Division of Hematology-Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of OtolaryngologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Bristol-Myers SquibbNew York CityUSA
  5. 5.Division of Hematology/OncologyUT Health Science Center at San Antonio Cancer Therapy & Research CenterSan AntonioUSA

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