Phase II Trial of Dasatinib in Patients with Metastatic Breast Cancer Using Real-Time Pharmacodynamic Tissue Biomarkers of Src Inhibition to Escalate Dosing
| Autor: | Erika Hamilton, Sarah S. Bacus, Christina I. Herold, Justin Favaro, P. Kelly Marcom, Bercedis L. Peterson, Renee Welch, Kimberly L. Blackwell, Gretchen Kimmick, Vijaya Chadaram, Judith O. Hopkins |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Oncology Cancer Research medicine.medical_specialty medicine.medical_treatment Proto-Oncogene Proteins pp60(c-src) Dasatinib Phases of clinical research Antineoplastic Agents Breast Neoplasms Kaplan-Meier Estimate Pharmacology Internal medicine Biomarkers Tumor Humans Medicine Neoplasm Metastasis Protein Kinase Inhibitors Aged Aged 80 and over Chemotherapy business.industry Cancer Middle Aged medicine.disease Metastatic breast cancer Thiazoles Pyrimidines Tolerability Female business Tyrosine kinase Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | Clinical Cancer Research. 17:6061-6070 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-11-1071 |
| Popis: | Purpose: A phase II study of dasatinib, an inhibitor of multiple oncogenic tyrosine kinases including Src, was conducted to evaluate 16-week progression-free rate and tolerability in patients with previously treated metastatic breast cancer (MBC). Real-time assessment of potential tissue biomarkers of Src inhibition was used to optimize dosing. Experimental Design: Eligibility criteria required that patients have measurable MBC, biopsiable tumor, and unlimited prior therapies. For the analysis of change in protein biomarkers of Src inhibition, focal adhesion kinase, paxillin, and p-Src, patients underwent metastatic biopsies at baseline and 4 weeks. Patients who tolerated the starting dose of dasatinib (50 or 70 mg orally twice daily) for the first 28-day cycle, and displayed suboptimal Src inhibition, were escalated to a higher dose (70 or 100 mg). Results: The trial was closed early with 31 patients because of a statistical boundary that required at least 4 (13%) patients without disease progression to continue accrual. These 31 patients had a median of 2 prior lines of chemotherapy for MBC. The most notable toxicity was pleural effusions in 16 patients (52%). Twenty patients had evaluable metastatic biopsies. None of the tumors showed the predefined optimal level of Src inhibition at week 4. Conclusions: Single-agent dasatinib did not exhibit significant antitumor activity in patients with heavily pretreated MBC. There were no clinically meaningful decreases before and after dasatinib exposure between exploratory tissue biomarkers of Src inhibition which may be attributable to challenges in defining biomarker endpoints for multitargeted tyrosine kinase inhibitors. Clin Cancer Res; 17(18); 6061–70. ©2011 AACR. |
| Databáze: | OpenAIRE |
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