Abstract P5-20-08: Phase II trial of ixabepilone (Ixa) and dasatinib (D) for treatment of metastatic breast cancer (MBC)

Background: Ixa is a novel semi-synthetic epothilone microtubule blocking agent with activity in taxane and anthracycline-resistant MBC. D is a potent small molecule tyrosine kinase inhibitor with substantial activity against SRC family non-receptor kinases, known to play multiple roles in promoting tumor growth and metastases. D inhibits cellular SRC autophosphorylation in cell lines that highly express SRC and inhibits in vivo activation in a broad array of tumors in nude mice. Ixa and D have synergistic effects in preclinical models suggesting this strategy would be of clinical benefit as combination therapy. A phase I trial of the combination determined the maximally tolerated doses of ixabepilone at 20 mg/m2 weekly and dasatinib 100 mg po daily with objective responses seen. Neutropenia was the dose limiting toxicity. Methods: Multicenter single arm phase II trial. Eligibility: Measurable or evaluable disease by RECIST 1.0, ECOG PS 0–2, HER2− or HER2 refractory, no CYP 3A4 inducers or inhibitors, no H2 blockers or PPIs, no pleural/pericardial effusion, exposure to 1 or 2 prior lines of chemotherapy in the metastatic setting, peripheral neuropathy ≤ grade 1. The primary endpoint was progression-free survival (PFS). Assessment for response was performed every 8 weeks. The treatment schedule was D at 100 mg po daily starting day 1, and Ixa 20 mg/m2 Day 1, 8, 15 every 28 days (1 cycle). Results: The study met its accrual goal with 50 patients (pts) enrolled on the phase II dosing, including six from the phase I portion. As of May 21, 2012, 47 pts are evaluable. The median age was 55 (range, 34–70), 19 African-American, 46 ECOG PS 0–1, median number of metastatic sites, three. Forty pts had prior taxanes, 24 prior anthracyclines. Median PFS was 6.0 months (95% CI, 2.9–8.0), achieving pre-specified value of interest for further study of the combination. The overall unconfirmed response rate was 14.9% with a clinical benefit rate (CR+PR + stable at 24 weeks) of 25.5%. Six pts continued D monotherapy after eight cycles of Ixa + D. All-grade adverse events (AEs) occurring in >15% of pts included anemia (45%), neutropenia (32%), nausea (51%), vomiting (32%) diarrhea (51%), fatigue (53%), anorexia (25%) dysgeusia (32%), headache (28%), peripheral neuropathy (34%) cough (28%) alopecia (21%) and hypokalemia (19%). Grade 3/4 adverse events occurred in 30 patients, with only four experiencing grade 4 AEs, three neutropenia and one chest pain. No grade 3/4 febrile neutropenia occurred. Grade 3 AEs of interest included two pts with peripheral neuropathy and 1 with pleural effusion. Conclusions: The combination of Ixabepilone weekly + Dasatinib orally daily is an active and well tolerated regimen in pretreated MBC with manageable toxicity. Updated results will be reported. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-08.