Dasatinib Plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy Data from Phase 1 Study CA180-004.

Abstract

Abstract Background: SRC is a potential therapeutic target in breast cancer and has a central role in hormone therapy resistance and in osteoclast activity. Dasatinib is a potent SRC inhibitor that inhibits breast cancer cell proliferation and migration in vitro, including synergy with 5FU in some cell lines, and inhibits osteoclast activity in clinical trials. CA180-004 is a phase 1 study designed to identify dose-limiting toxicities (DLT) and recommended phase 2 doses of dasatinib plus capecitabine in women with advanced breast cancer (ABC). Safety and efficacy data are now reported with additional follow-up.Methods: Cohorts of pts with ABC were treated at four dose levels (DL) with capecitabine (mg/m2 twice daily [BID] on D1-14 of 21-day cycles) and dasatinib (mg daily): DL1: capecitabine 825 + dasatinib 50 BID; DL2: capecitabine 825 + dasatinib 70 BID; DL3: capecitabine 1000 + dasatinib 70 BID; DL3a: capecitabine 1000 + dasatinib 100 once daily (QD). All pts had performance status 0-1, prior taxane and/or anthracycline and ≤2 prior chemotherapy-containing regimens for advanced disease. Disease assessments were performed every 6 weeks. DL3a was expanded for further safety and efficacy estimate using best objective response and progression-free survival (PFS) rates.Results: To date, 47 pts with ABC have been treated, 31 in escalation phase plus 16 in expansion (5 too early). Median age was 52 years (range 35-77). Tumor subtypes: 14% were Her2-amplified, 57% ER+ or PR+, 29% triple-negative. Safety was previously reported (ASCO 2009) for escalation phase; no MTD was defined based on DLTs. Of 20 evaluable pts in DL3a, 2 DLTs have been observed: 1 pneumonia, pain and pleural effusion plus 1 diarrhea, neutropenia, vomiting, mucositis and anemia. The most common drug-related adverse events (AEs, any grade) were headache, fatigue/asthenia, nausea/vomiting, diarrhea, hand-foot syndrome (HFS) and pleural effusion. The most common grade 3/4 AEs were fatigue/asthenia, HFS, vomiting and diarrhea. To date, 19 have remained on treatment ≥4 months, including 3 for >1 year. Median duration of treatment (n=42) was 13 weeks; 23 pts have discontinued for progression and 7 for toxicity. Of 38 pts with on-study assessment, 6 had confirmed partial response (treatment durations 17+, 23, 25, 36+, 71, 73 wks), 6 had unconfirmed partial or clinical response (5, 11, 13, 18, 23+, 24 wks), and 9 had prolonged stable disease (16+, 17, 23+, 24+, 25+, 29, 39+, 48+, 63+ wks). Updated efficacy data, including PFS by hormone receptor status, will be presented.Conclusions: Dasatinib and capecitabine combination treatment was well tolerated and encouraging efficacy was observed. Further assessment of this combination is warranted. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3092.