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Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing.

Publication ,  Journal Article
Herold, CI; Chadaram, V; Peterson, BL; Marcom, PK; Hopkins, J; Kimmick, GG; Favaro, J; Hamilton, E; Welch, RA; Bacus, S; Blackwell, KL
Published in: Clin Cancer Res
September 15, 2011

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.

Duke Scholars

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 15, 2011

Volume

17

Issue

18

Start / End Page

6061 / 6070

Location

United States

Related Subject Headings

  • Thiazoles
  • Pyrimidines
  • Proto-Oncogene Proteins pp60(c-src)
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Middle Aged
  • Kaplan-Meier Estimate
  • Humans
  • Female
 

Citation

APA
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MLA
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Herold, C. I., Chadaram, V., Peterson, B. L., Marcom, P. K., Hopkins, J., Kimmick, G. G., … Blackwell, K. L. (2011). Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing. Clin Cancer Res, 17(18), 6061–6070. https://doi.org/10.1158/1078-0432.CCR-11-1071
Herold, Christina I., Vijaya Chadaram, Bercedis L. Peterson, P Kelly Marcom, Judith Hopkins, Gretchen G. Kimmick, Justin Favaro, et al. “Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing.Clin Cancer Res 17, no. 18 (September 15, 2011): 6061–70. https://doi.org/10.1158/1078-0432.CCR-11-1071.
Herold CI, Chadaram V, Peterson BL, Marcom PK, Hopkins J, Kimmick GG, et al. Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing. Clin Cancer Res. 2011 Sep 15;17(18):6061–70.
Herold, Christina I., et al. “Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing.Clin Cancer Res, vol. 17, no. 18, Sept. 2011, pp. 6061–70. Pubmed, doi:10.1158/1078-0432.CCR-11-1071.
Herold CI, Chadaram V, Peterson BL, Marcom PK, Hopkins J, Kimmick GG, Favaro J, Hamilton E, Welch RA, Bacus S, Blackwell KL. Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing. Clin Cancer Res. 2011 Sep 15;17(18):6061–6070.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 15, 2011

Volume

17

Issue

18

Start / End Page

6061 / 6070

Location

United States

Related Subject Headings

  • Thiazoles
  • Pyrimidines
  • Proto-Oncogene Proteins pp60(c-src)
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Middle Aged
  • Kaplan-Meier Estimate
  • Humans
  • Female