Phase 1 pharmacokinetic and drug‐interaction study of dasatinib in patients with advanced solid tumors
Open Access
- 27 January 2010
- Vol. 116 (6), 1582-1591
- https://doi.org/10.1002/cncr.24927
Abstract
BACKGROUND: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once‐daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose‐limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. Cancer 2010. © 2010 American Cancer Society.Keywords
This publication has 22 references indexed in Scilit:
- Inhibition of Src Family Kinases with Dasatinib Blocks Migration and Invasion of Human Melanoma CellsMolecular Cancer Research, 2008
- Src family kinases as mediators of endothelial permeability: effects on inflammation and metastasisCell and tissue research, 2008
- Targeting Src Family Kinases Inhibits Growth and Lymph Node Metastases of Prostate Cancer in an Orthotopic Nude Mouse ModelCancer Research, 2008
- Src Family Nonreceptor Tyrosine Kinases as Molecular Targets for Cancer TherapyAnti-Cancer Agents in Medicinal Chemistry, 2007
- Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasionMolecular Cancer Therapeutics, 2007
- Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinibMolecular Cancer Therapeutics, 2006
- Inhibition of Src Expression and Activity Inhibits Tumor Progression and Metastasis of Human Pancreatic Adenocarcinoma Cells in an Orthotopic Nude Mouse ModelThe American Journal of Pathology, 2006
- Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non–Small Cell Lung Cancer CellsClinical Cancer Research, 2005
- Inhibition of Src Tyrosine Kinase as Treatment for Human Pancreatic Cancer Growing Orthotopically in Nude MiceClinical Cancer Research, 2004
- Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer.JCI Insight, 1993