Abstract 4714: Phase I/II trial of ixabepilone (Ixa) and dasatinib (D) for treatment of metastatic breast cancer (MBC)

Abstract

Abstract Background: Ixa is a novel microtubule blocking epothilone 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. D was safe as a single agent in MBC with modest single agent activity. Ixa and D have synergistic effects in preclinical models suggesting this strategy would be of clinical benefit as combination therapy. Methods: Open label multicenter dose escalation trial determining the maximally tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the combination of Ixa + D followed by a phase II component evaluating efficacy. In phase I, up to four dose range cohorts were planned. In each dose level (DL), three patients (pts) initially enrolled and escalated until > 1/3 pts on a DL exhibited DLT. The MTD was defined at the DL at which < 1/6 pts experienced DLT. Eligibility included MBC previously treated with 1-2 prior lines of therapy, Grade < 1 peripheral neuropathy, ability to take oral medications, HER2- or HER2-directed therapy resistant, ECOG PS 0-2, no pleural/pericardial effusions, QTc interval <450 msec. DL 0 was Ixa 16 mg/m2 IV day 1, 8, 15 of a 28-day cycle with D100 mg QD PO daily. DL 1: Ixa 20 mg/m2; D100 mg QD; DL2: Ixa 20 mg/m2; D140 mg QD. Adverse event grading by CTCAE 3.0. Results: Twelve pts were treated during the phase I portion, 3 at DL 0, 6 at DL 1 and 3 at DL 2. Median age was 52.3, 25% African-American, ECOG 0 three pts, ECOG 1, 9 pts. Prior chemotherapy: 10 received two lines, 2 one line. The MTD was established at DL 1, Ixa 20 mg/m2 day 1, 8, 15, and D 100 mg QD daily Q 28 days. At DL 2, DLT of leucopenia and thrombocytopenia occurred in 2 patients. Grade 3 non-hematologic adverse events occurring in >1 pt included diarrhea in 2 and fatigue in 2. No grade 4 non-hematologic toxicity was seen. One pt developed grade1 pleural effusion and 2 had grade 1/2 peripheral neuropathy. Other grade 1/2 AEs included rash, cough, dyspnea, muscle pain, pyrexia and anorexia. 2/12 pts achieved a partial response (25%) and 4 (33%) achieved stable disease. Two pts remain on study at cycle 10+ and at cycle 7+. Dose delays /reductions were not required during DL 0 until cycle 4 but dose delays occurred from cycle 1 onward in DL 1 and 2. Conclusions: Ixa + D can be safely delivered at clinically relevant doses to pts with MBC. A MTD of Ixa at 20 mg/m2 weekly 3/4 wks and D at 100 mg QD was established with clinical activity seen at this dose level. The phase II portion is actively accruing pts. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4714. doi:10.1158/1538-7445.AM2011-4714