title: Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. cherold@bidmc.harvard.edu
authors.forename: Christina I
authors.initials: CI
authors.lastname: Herold
authors.forename: Vijaya
authors.initials: V
authors.lastname: Chadaram
authors.forename: Bercedis L
authors.initials: BL
authors.lastname: Peterson
authors.forename: P Kelly
authors.initials: PK
authors.lastname: Marcom
authors.forename: Judith
authors.initials: J
authors.lastname: Hopkins
authors.forename: Gretchen G
authors.initials: GG
authors.lastname: Kimmick
authors.forename: Justin
authors.initials: J
authors.lastname: Favaro
authors.forename: Erika
authors.initials: E
authors.lastname: Hamilton
authors.forename: Renee A
authors.initials: RA
authors.lastname: Welch
authors.forename: Sarah
authors.initials: S
authors.lastname: Bacus
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Blackwell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000069439:Dasatinib; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016392:Proto-Oncogene Proteins pp60(c-src); D000069439:Dasatinib