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Published on: September 30, 2016
Phase I and pharmacokinetic study of dasatinib and cetuximab in patients with advanced solid malignancies
Athanassios Argiris1, Trevor M Feinstein, Lin Wang
1Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Argiris@uthscsa.edu
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.
Insights
Combining dasatinib (SFK inhibitor) and cetuximab (anti-EGFR antibody) showed promise for advanced solid tumors. Starting dasatinib after cetuximab reduced early-onset headaches, recommending 150 mg daily for phase II studies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Combined inhibition of epidermal growth factor receptor (EGFR) and Src family kinases (SFK) may improve therapeutic outcomes in cancer.
- This study evaluated the combination of dasatinib, a multi-targeted kinase inhibitor, and cetuximab, a monoclonal antibody targeting EGFR.
Purpose of the Study:
- To assess the safety and tolerability of combined dasatinib and cetuximab in patients with advanced solid malignancies.
- To determine the recommended dose of dasatinib for phase II studies when administered with cetuximab.
- To investigate the impact of administration timing on toxicity, specifically early-onset headache.
Main Methods:
- A phase I dose-escalation study involving 25 patients with advanced solid malignancies.
- Patients received weekly intravenous cetuximab and daily oral dasatinib at three dose levels (100 mg, 150 mg, 200 mg).
- Pharmacokinetic and pharmacodynamic assessments of dasatinib were conducted, along with toxicity monitoring.
Main Results:
- The combination was generally tolerated, with dose-limiting toxicities including headache and nausea observed at higher dasatinib doses.
- Common grade 3-4 toxicities included dyspnea, vomiting, nausea, hypersensitivity reactions, headache, and anemia.
- Early-onset headache, occurring after cetuximab loading, was significantly reduced when dasatinib administration was delayed by three days.
- Dasatinib pharmacokinetics and SFK inhibition were not significantly altered by concurrent cetuximab treatment.
Conclusions:
- Dasatinib 150 mg once daily in combination with weekly cetuximab is recommended for further phase II investigation.
- Administering dasatinib after the cetuximab loading dose effectively ameliorates early-onset headache.
- The combination demonstrates a potential therapeutic strategy for advanced solid tumors, warranting further clinical evaluation.