Phase II Study of Paclitaxel and Dasatinib in Metastatic Breast Cancer

Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We conducted a phase II trial in patients with HER2-negative metastatic breast cancer receiving weekly paclitaxel and theSRCinhibitor dasatinib (120mgdaily). The primary end point was response according to Response Evaluation Criteria in Solid Tumors and secondary end points included progression-free survival (PFS) and overall survival (OS). We enrolled 40 patients, including 2 men, but the study was stopped early because of slow accrual. The overall response rate was 23%. The median PFS and OS was 5.2 (95% confidence interval [CI], 2.9-9.9) and 20.6 (95% CI, 12.9-25.2) months, respectively. Toxicities were as expected and included fatigue, neuropathy, and diarrhea. We were unable to find any predictive biomarker of treatment benefit. Background: Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial. Patients and Methods: Patients had received <= 2 chemotherapy regimens for measurable, HER2-negative MBC. Patients received paclitaxel and dasatinib (120 mg daily) and were assessed according to Response Evaluation Criteria in Solid Tumors for overall response rate (ORR), the primary end point. Secondary end points included progression-free survival (PFS) and overall survival (OS). A 30% ORR (n = 55) was deemed worthy of further investigation. Exploratory biomarkers included N-telopeptide (NTX) and plasma vascular epidermal growth factor (VEGF) receptor 2 as predictors of clinical benefit. Results: From March 2010 to March 2014, 40 patients, including 2 men enrolled. The study was stopped early because of slow accrual. Overall, 32 patients (80%) had estrogen receptor-positive tumors and 23 (58%) had previously received taxanes. Of the 35 assessable patients, 1 (3%) had complete response and 7 (20%) partial response, resulting in an ORR of 23%. The median PFS and OS was 5.2 (95% confidence interval [CI], 2.9-9.9) and 20.6 (95% CI, 12.9-25.2) months, respectively. As expected, fatigue (75%), neuropathy (65%), and diarrhea (50%) were common side effects, but were generally low-grade. Median baseline NTX was similar in patients who had clinical benefit (8.2 nmol BCE) and no clinical benefit (10.9 nmol BCE). Similarly, median baseline VEGF levels were similar between the 2 groups; 93.0 pg/mL versus 83.0 pg/mL. Conclusion: This phase II study of dasatinib and paclitaxel was stopped early because of slow accrual but showed some clinical activity. Further study is not planned. (C) 2018 Elsevier Inc. All rights reserved.