Phase Ib study of eribulin (ERB) and cyclophosphamide (CTX) in metastatic breast cancer (MBC).

Abstract

1095 Background: ERB is a non-taxane microtubule inhibitor approved for the treatment (Tx) of taxane (TAX) and anthracycline-treated MBC based on improved OS compared to treatment of physician choice. In the adjuvant setting, docetaxel/CTX (TC) was superior to doxorubicin/CTX for DFS and OS. ERB is active in TAX-resistant disease with a low rate of peripheral neuropathy (PN); its primary dose-limiting toxicity (DLT) is bone marrow suppression. We hypothesized that the combination of ERB and CTX would be well tolerated and active in patients with TAX-resistant disease, with potential applicability to the adjuvant setting. Methods: We designed a 3+3 phase Ib study of ERB, administered in 2 escalating doses on day 1 and 8, with CTX 600 mg/m2day 1 every 21 days. Eligibility included PN ≤ grade 1. Correlative studies to identify predictors of response and toxicity included whole blood for SNPs, GWAS, circulating tumor cells (CTC), and archived tumor RNA/protein expression analysis. Toxicity assessment included QoL and evaluation of PN. Results: 6 patients (pts) with MBC, median age 50 (47-63), were enrolled. All pts had prior TAX exposure and 4 pts had baseline grade 1 PN. Tumor characteristics included hormone receptor + (5 pts), HER2+ (2 pts), and triple-negative (1 pt). Median number of prior Tx for MBC was 5 (1-8). No DLTs were observed; the RP2D is eribulin 1.4 mg/m2 on D1 and D8 with CTX D1 600mg/m2. Neutropenia was the only G3/G4 non-DLT observed at this dose, requiring GCSF support in cycle1 in 2 of 3 pts. All grade toxicities included neutropenia (50%), thrombocytopenia, fatigue, nausea, PN, rash, mucositis, alopecia (33% each), and elevated liver enzymes (17%). Pts received a median of 5.5 cycles (range 3-13), with 3 pts still on Tx. Responses included 2PRs (33%) and 4 SD (67%). 2 pts stopped study Tx for QoL and continued ERB alone. Only 2 pts met threshold of >5CTC/7.5ml at baseline; these had a mean decrease of 90.5% at the start of cycle 2. Conclusions: ERB and CTX is a well-tolerated regimen with promising activity in MBC, with the primary toxicity being neutropenia requiring growth factor support. A phase II study in MBC is underway. Additional correlative studies are ongoing including molecular analyses of CTC. Clinical trial information: NCT01554371.