Dasatinib Plus Capecitabine for Advanced Breast Cancer: Safety and Preliminary Efficacy in Phase I Study CA180004
Mené sur 52 patientes atteintes d'un cancer du sein de stade avancé, cet essai de phase I évalue la dose maximale tolérée du dasatinib, en combinaison avec la capécitabine, et ses effets sur des biomarqueurs de l'angiogenèse
Purpose: Dasatinib is a Src-family kinase inhibitor with modest activity in advanced breast cancer (ABC). 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 (BID; DL1), 70 mg BID (DL2 and DL3), or 100 mg daily (QD; DL3a), plus capecitabine on days 1-14 of a 21-day cycle, at 825 mg/m2 BID (DL1 and DL2) or 1000 mg/m2 BID (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 (AEs) 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 1000 mg/m2 BID, and Dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response (PR) was noted in 24% and stable disease (SD) 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 was observed. Conclusions: Dasatinib 100 mg once daily plus capecitabine 1000 mg/m2 BID were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect.