Background: Two phase III trials have demonstrated the efficacy of eribulin monotherapy in patients with metastatic breast cancer (MBC) who have progressed after previous anthracycline and taxane chemotherapy. Capecitabine is also an effective agent in patients with MBC. A phase Ib dose-escalation study has investigated two dosing schedules of eribulin in combination with capecitabine to determine the recommended phase II dose. The aims of this open-label, non-randomized, phase II, dose-confirmation study were to determine efficacy and safety of this combination in patients with MBC. Interim data to April 2014 are provided here; final results will be presented at the meeting. Methods: Eligible patients were females with MBC who had received up to 3 previous chemotherapy regimens in any setting (including an anthracycline and a taxane, but excluding capecitabine), an ECOG performance status (PS) ≤1, and adequate hematological, renal and hepatic function (at study entry, 20 [47.6%] patients had liver metastases; 24 [57.1%] had lung metastases). Patients received 1.4 mg/m2 eribulin mesylate (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) i.v. on days 1 and 8 plus oral capecitabine 1000 mg/m2 b.i.d. on days 1–14 (21-day cycles) until disease progression, unacceptable toxicity or death. Disease assessments (CT scans) were performed every 6 weeks. The primary outcome was the objective response rate (ORR); secondary outcomes included clinical benefit rate (CBR), progression-free survival (PFS), and safety and tolerability. Results: 42 females (median age: 52.5 years [range: 32–74]; ECOG-PS of 0: n = 18 [42.9%]) were enrolled; patients received study drug as a 1st-line (23.8% [n = 10]), 2nd-line (45.2% [n = 19]) or ≥3rd-line (31.0% [n = 13]) chemotherapy. A median of 8 (range: 1–30) treatment cycles were administered (59.5% of patients received ≥6 cycles), with 94.4% of eribulin doses and 94.5% of capecitabine doses given as planned. The ORR was 42.9% and the CBR was 57.1% (Table), with a median PFS of 7.1 months (95% CI: 4.4, 9.8). The most common grade 3/4 adverse events (AEs) were neutropenia (66.7%), leukopenia (14.3%), febrile neutropenia (7.1%) and anemia, fatigue, nausea and peripheral sensory neuropathy (each 4.8%). AEs of special interest (any grade) included: hand–foot syndrome (26.2%), peripheral neuropathy (23.8%), and diarrhea (21.4%). The incidences of AEs leading to study drug dose adjustment were: 47.6% of patients (dose interruption), 42.9% (dose reduction), and 2.4% (drug withdrawal). Table: Tumor response (investigator assessment)PatientsN = 42n (%)n (%)Complete response (CR)2 (4.8)Partial response (PR)16 (38.1)Stable disease (SD)16 (38.1)Progressive disease (PD)3 (7.1)Not evaluable5 (11.9)Objective response rate (CR + PR)18 (42.9)95% CI27.7, 59.0Clinical benefit rate (CR + PR + SD ≥ 6 months)24 (57.1)95% CI41.0, 72.3 Conclusions: This phase II study suggests that eribulin in combination with capecitabine is efficacious in patients with MBC, with a safety and tolerability profile consistent with previous data. Phase III studies of this combination in patients with MBC are warranted. Citation Format: Chris Twelves, Muhammad Y Nasim, Alan Anthoney, Claudio I Savulsky, Shuxin Yin, TR Jeffry Evans. Efficacy and safety of eribulin in combination with capecitabine in patients with metastatic breast cancer: an open-label, phase II dose-confirmation study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-04.

2552 Background: Eribulin mesylate is a microtubule dynamics inhibitor approved by FDA for patients (pts) with metastatic breast cancer after treatment with at least two prior chemotherapeutic regimens. This Phase Ib, open-label dose-escalation study determined the maximum tolerated dose (MTD) of eribulin in combination with capecitabine. Methods: Pts with advanced solid malignancies refractory to standard therapies, adequate organ function and ECOG performance status ≤2 received eribulin mesylate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 mg/m2 on Day 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on Days 1 and 8), in combination with twice-daily oral capecitabine 1000 mg/m2 Days 1-14 every 21 days. The MTD was defined as the highest dose in each schedule where ≤1/6 pts experienced dose-limiting toxicity (DLT). Safety and pharmacokinetics (PK) were assessed. Results: Of the 34 pts recruited, 19 (53% male; median age 62 years; 42% ECOG 0, 58% ECOG 1) and 15 (33% male; median age 61 years; 33% ECOG 0, 60% ECOG 1, 7% ECOG 2) were enrolled in Schedules 1 and 2, respectively. Most common tumor types were large intestine (20.6%), lung/bronchus (17.7%) and breast (14.7%). DLTs are shown in the table; there were no unexpected toxicities with the combination. The MTD for eribulin mesylate was 1.6 and 1.4 mg/m2 for Schedules 1 and 2, respectively, in combination with capecitabine 1000 mg/m2 twice-daily. Eribulin PK were dose proportional and independent of schedule or capecitabine co-administration. Combination with eribulin had no effect on the disposition of capecitabine and its metabolites. Although sample size was small, preliminary signs of efficacy were observed. Conclusions: The combination of eribulin and capecitabine was well tolerated with no unexpected safety findings. Schedule 2 MTD (1.4 mg/m2 Days 1 and 8) delivered a higher dose intensity of eribulin than Schedule 1 and was selected for evaluation in an ongoing Phase II breast cancer study. [Table: see text]

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