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

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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. Conclusion:s Dasatinib 150 mg once daily plus weekly cetuximab is recommended for phase II studies. Early-onset headache was ameliorated by starting dasatinib after cetuximab.

Original languageEnglish (US)
Pages (from-to)1575-1584
Number of pages10
JournalInvestigational New Drugs
Volume30
Issue number4
DOIs
StatePublished - Aug 1 2012

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Keywords

  • Cetuximab
  • Dasatinib
  • Epidermal growth factor receptor
  • Pharmacodynamic
  • Pharmacokinetic
  • Phase I
  • Src

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Argiris, A., Feinstein, T. M., Wang, L., Yang, T., Agrawal, S., Appleman, L. J., Stoller, R. G., Grandis, J. R., & Egloff, A. M. (2012). Phase i and pharmacokinetic study of dasatinib and cetuximab in patients with advanced solid malignancies. Investigational New Drugs, 30(4), 1575-1584. https://doi.org/10.1007/s10637-011-9732-3