Abstract P5-20-07: Phase II Trial of Dasatinib in Combination With Weekly Paclitaxel for Patients with Metastatic Breast Carcinoma
Authors: Morris PG , Lake D , McArthur HL , Gilewski T , Dang C , Chaim J , Patl S , Lim K , Norton L , Hudis CA , Fornier MN 
Published: August 2014

Abstract
Background: Src kinase plays an important role in proliferation, survival, angiogenesis and metastasis in several malignancies including breast cancer. Therefore, inhibition of Src and other tyrosine kinases (TKs) represents a novel therapeutic approach. Dasatinib is a potent inhibitor of 5 oncogenic TKs, inhibits VEGF-stimulated proliferation, has potent bone anti-resorptive activity and selectively inhibits basal-type breast cancer growth. Preclinically, the combination of dasatinib and paclitaxel had superior antitumor activity to either agent alone. In a previous phase I study, we determined that, in combination with weekly paclitaxel, the optimum dose of dasatinib was 120mg. Of note, 4/9 (44%) patients treated at or above this dasatinib dose level had objective tumor response. We now present results from the phase II trial of this combination.
Methods: Patients with MBC, ECOG PS 0–1, normal hepatic, renal, marrow function were eligible. Patients had measurable, HER2-negative metastatic breast cancer (MBC), ≤2 prior therapies for MBC. Treatment consisted of weekly paclitaxel 80 mg/m2 IV 3/4 weeks + Dasatinib 120mg orally daily. Response was assessed by RECIST after every 8 weeks of therapy. Simon's two-stage optimal design was used to test the null hypothesis of a 15% response rate (RR) against the alternative of a 30% RR. In stage I, planned enrollment was 23 patients based on Type I and Type II errors of 10%. If 4 or more responses are observed, enrollment will be extended to 55 patients. Exploratory correlative biomarkers of clinical benefit include Src phosphorylation (p-Src) in peripheral blood mononuclear cells, plasma levels of VEGFR2 and collagen Type IV, circulating tumor cells (CTCs) and tumor gene expression profiling.
Results: 21 patients (19 females, 2 male) have enrolled; median age 48 (range 30–79). Patients received a median of 1 prior therapy for MBC (range 0–2). 6 patients are not assessable for response: 1 has received &lt;8 weeks treatment, 5 came off study for toxicity (2 hypersensitivity reaction to paclitaxel, 1 infection, 1 diarrhea/nausea, 1 bleeding likely related to anticoagulation). Among the 15 patients assessable for response, best response to date is as follows: 2 (13%) patients partial response, 11 (73%) patients stable disease (SD) and 2 (13%) patients progression of disease. Of patients with SD, 6/11 (55%) continue on treatment after median of 2 months (range 2–10) and 5/11 (45%) patients have come off study after median of 10 months (range 3–21). Most toxicities have been hematological and low grade. Diarrhea and neuropathy have generally been low grade and no new toxicities related to the combination have occurred since expansion into the phase II. Potential biomarkers of clinical benefit including, p-Src, VEGFR2, collagen Type IV, and CTCs will be presented.
Conclusion: Data from this phase II has demonstrated preliminary evidence of activity for weekly paclitaxel and dasatinib 120mg in patients with MBC. These findings are consistent with data from this dose level in the earlier phase I study. Predictive biomarkers of clinical benefit are under investigation.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-07.