Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004

Abstract

1012 Background: SRC family kinases (SFK) mediate numerous signal-transduction pathways relevant to breast cancer as well as osteoclast function. Dasatinib, a potent oral inhibitor of SFK and other kinases has preclinical activity in breast models and in vitro synergy with Cap in some breast cancer cell lines (KPL-4 and HCC-70). A phase I trial of dasatinib plus Cap was conducted to define dose-limiting toxicities (DLT), maximum tolerated (MTD), and recommended phase II (RP2D) doses. Methods: Sequential cohorts of pts with ABC were treated with Cap twice daily (BID) on days 1–14 and dasatinib daily in 21-day cycles using dose levels (DL) for Cap (mg/m2) and dasatinib (mg): DL1: Cap 825 + dasatinib 50 BID; DL2: Cap 825 + dasatinib 70 BID; DL3: Cap 1000 + dasatinib 70 BID; DL3a: Cap 1000 + dasatinib 100 once daily (QD). All pts had ECOG performance status 0–1, had prior anthracycline and/or taxane, and received ≤2 regimens in advanced setting. MTD was based on DLT in first cycle and RP2D also based on tolerability of additional cycles. Results: 31 pts with ABC, median age 53 years (range 36–78) were treated. Number of pts treated/evaluable for DLT/reported DLT (event) were DL1: 7/6/1 (headache, grade 3); DL2: 9/7/0; DL3: 6/6/1 (diarrhea, grade 3), and DL3a: 9/9/1 (pneumonia, grade 3). Most frequent AEs related to either drug and occurring at any time on study (n pts) were nausea (12), vomiting (7), diarrhea (6), abdominal pain (2), fatigue (8), headache (7), musculoskeletal pain (1), and pleural effusion (4); hand-foot syndrome (5) was as expected for Cap alone. 11 patients experienced a Grade 3–4 non-hematologic AE at some point during the study. Laboratory abnormalities were uncommon. To date, 20 pts have continued treatment for ≥6 weeks and 9 pts for ≥12 weeks. Number of pts who (at any time) reduced dasatinib/reduced Cap/discontinued for toxicity were DL1: 2/2/1; DL2 2/2/3; DL3: 2/1/2; DL3a: 0/1/1. Updated safety and efficacy data will be presented. Conclusions: Dasatinib + Cap was tolerated without unexpected combined-treatment toxicity; few pts required dose reduction in later cycles. The recommended phase II dose, Cap 1000 plus dasatinib 100 QD, is well tolerated and will be studied for efficacy in an expanded patient cohort. [Table: see text]