A phase II study to optimize dasatinib dosing in metastatic breast cancer patients using real-time pharmacodynamic tissue and urinary biomarkers.
Authors: CI Herold, PK Marcom, J Hopkins, EA McKeen, RA Welch, V Chadaram, J Spohn, C Ung, S Bacus, BL Peterson, KL Blackwell
Journal: Cancer Research (2009)

Abstract Abstract #3123 Background: In order to optimize drug efficacy and patient selection for targeted agents such as dasatinib, a tyrosine kinase inhibitor, there is a need for adaptive trial methodologies and validated marker endpoints. Predictive and pharmacodynamic (PD) biomarkers of dasatinib activity will be crucial for individualized drug dosing and enrichment of patient populations treated with the drug. Multiple potential predictive and PD markers exist for dasatinib including active/total Src, active/total EphA2, and downstream targets of Src such as focal adhesion kinase (FAK) and paxillin (pax). Given Src's role in bone modeling, markers of bone resorption may also serve as important biomarkers. We designed a phase II trial in metastatic breast cancer (MBC) wherein real-time assessment of these potential biomarkers is used to optimize the dose and anti-tumor effects of dasatinib.&amp;#x2028; Material and methods: Key eligibility includes patient with MBC, ECOG 0-1, unlimited prior therapies, and biopsiable tumor. Patients with bone-only MBC were excluded due to tissue quality required for PD analysis. Metastatic biopsies at baseline and week 4 of dasatinib therapy were analyzed using quantitative immunohistochemistry (IHC) (measured in optical densitometry (OD) units) for the following markers: phospho-Src (p-Src), phospho-FAK (p-FAK) and phospho-pax (p-pax). For patients who tolerated the starting dose of dasatinib (50 mg bid), and displayed suboptimal Src inhibition (&amp;lt;80% inhibition of phosphorylation of either biomarker), dasatinib dosing was escalated at week 4 to 70 mg bid. Urinary N-telopeptide (NTX), a marker of bone resorption, was measured monthly.&amp;#x2028; Results: Since 12/2007, 12 patients have enrolled and 8 have evaluable, paired metastatic biopsies. Of the other 4 patients, 2 withdrew due to toxicity, 1 voluntarily withdrew, and 1 patient has not yet reached week 4. There has been one case of dyspnea related to possible drug toxicity. Other grade 3/4 toxicities are as follows: anorexia (3), pleural effusion (1), DVT (1). All eligible patients underwent dasatinib dose escalation at week 4 based on their individual tumor biomarker results. All tumors displayed some level of Src inhibition but none of the tumors reached the pre-defined "optimal" level of Src inhibition at week 4; the median changes in tissue biomarker levels are as follows: p-FAK -20%, p-pax -13%, p-Src -9%, and urinary NTX level -11%.&amp;#x2028; Conclusions: Our initial analysis of sequential tumor biopsies collected in a phase II trial of single-agent dasatinib in MBC illustrates that real-time biomarkers will both optimize the dosing of targeted agents and define potential on- and off-target drug effects. Accrual is ongoing and updated results of all biomarker endpoints as well as efficacy and toxicity data will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3123.