Dasatinib plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy in Phase I Study CA180004

Abstract

Purpose: Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis.Experimental Design: Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m 2 twice daily (DL1 and DL2) or 1,000 mg/m 2 twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis.Results: Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor-positive. Most common adverse events (AE) were any grade nausea (58%), hand-foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand-foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m 2 twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed. Conclusions: Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m 2 twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect.

Src Inhibition Can Synergize with Gemcitabine and Reverse Resistance in Triple Negative Breast Cancer Cells via the AKT/c-Jun Pathway

“…Several clinical studies have evaluated the use of selective src inhibitors like Dasatinib or Saracatinib for treating breast cancer [14, 15]. Preclinical data demonstrated saracatinib decreased cell growth and migration in MDA-MB-231 breast cancer cell line and xenograft models, however, it was later shown to be ineffective as single agent therapy in clinical trials [16, 17].…”

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

“…A combination of dasatinib and capecitabine or gemcitabine has been shown to have potential for the treatment of breast cancer. 21,22) Taking into account the phase 2 clinical trials of gefitinib and dasatinib against breast cancer, we speculated that there would be a synergistic effect of dasatinib or gefitinib combined with the antimetabolite drug cladribine in the treatment of breast cancer. …”

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

“…82 Combination trials have shown improved outcomes in patients with breast cancer, for example Phase I clinical trials of dasatinib with Capecitabine show clinical response rates of 56% in unselected patients. 83 Other trials combining dasatinib with paclitaxel 84 and bosutinib with exemestane 85 are currently underway in patients with advanced metastatic breast cancer and are showing improved responses compared to single agents alone. These preliminary results suggest that the efficacy of SFK inhibitors will likely be improved by combining these drugs with others that increase potency or have parallel cytotoxic activity.…”