Study design and patients. GIM11-BERGI is a phase II, multicenter, single-arm study following a Simon’s two-stage optimal design . All patients enrolled in the study received eribulin 1,23 mg/m2 on days 1 and 8 every 3 weeks intravenously combined with bevacizumab 15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks intravenously, depending on the patient’s or physician’s preference (Figure 1). Study treatment was continued until disease progression, unacceptable toxicity, or patient withdrawal. If patients discontinued bevacizumab or eribulin for any reason before disease progression, the other treatment was continued as monotherapy until disease progression, unacceptable toxicity, or patient withdrawal. In the event of toxicity, neither dose reduction nor modification of bevacizumab was allowed, but bevacizumab was to be interrupted or permanently discontinued in case of hypertension, proteinuria, thrombosis, embolism, hemorrhage, congestive heart failure or wound-healing complications.
Eligible women were those aged 18 years or older who had an HER2-negative breast cancer with documented progression of disease after or during first-line chemotherapy-based treatment with paclitaxel combined with bevacizumab for metastatic disease. Patients must have had a measurable disease per RECIST v1.1 criteria  according to investigator assessment. Patients with hormone receptor (HR)-positive disease may have been treated with one or more lines of endocrine-based therapy before receiving paclitaxel or bevacizumab. In addition, as part of their first line maintenance treatment, patients may have received bevacizumab monotherapy, bevacizumab plus endocrine treatment or no treatment (for ≤ 6 weeks from the last bevacizumab administration).
All eligible patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and an estimated life expectancy of 12 weeks or more. Patients were ineligible if they had previously received (i) first-line anti-angiogenic therapy (e.g. tyrosine kinase inhibitors [TKIs] or anti-vascular endothelial growth factors [anti-VEGFs]) other than bevacizumab for the first-line treatment of metastatic breast cancer; (ii) if they had exclusively received endocrine therapy combined with bevacizumab for the first-line treatment of metastatic breast cancer; positive or unknown HER2 status; (iii) inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg) while receiving antihypertensive medication; (iv) a serious non-healing wound, active ulcer, or untreated bone fracture; (v) New York Heart Association Class II or greater congestive heart failure; pulmonary lymphangitis or pulmonary dysfunction requiring active treatment, including the use of oxygen; pre-existing grade ≥2 neuropathy; (vi) serious active infection requiring intravenous antibiotics and/or hospitalization at study entry; (vii) history of hypertensive crisis, hypertensive encephalopathy, nephrotic syndrome, bleeding diathesis, clinically relevant coagulopathy, or grade 3 or 4 venous thromboembolism, and lastly (viii) a history of myocardial infarction, unstable angina, stroke or transient ischemic attack (TIA), significant vascular disease, gastrointestinal perforation, abdominal fistula, intra-abdominal abscess, or active gastrointestinal bleeding within 6 months preceding study treatment. Patients were also ineligible if they had inadequate hematological function, coagulation parameters, hepatic function or renal function.
Statistical Analyses. A Simon’s two-stage optimal design  was adopted to define the total number of patients required for this phase II study. An overall clinical response rate of 25% as the target activity level and 12% as the lowest response rate of interest were considered. The study was designed to have 80% power to accept the hypothesis and a 5% significance to reject the hypothesis. Therefore, the probability of accepting a therapy with a real response rate below12% and the risk of rejecting a treatment with a response rate 25% would be, in both cases, less than 5%.
At the first stage, and in order to proceed to stage II, 19 patients were monitored for a minimum of 18 weeks (corresponding to 6 cycles of study treatment). If there were fewer than 3 responses in the initial 19 patients, the study would have been stopped. Otherwise, 42 additional patients were planned to be accrued for a total of 61 patients. At the second stage, at least 12 objective responses in the 61 patients enrolled were required for this regimen to be deemed worthy of further investigation. At the second stage, patients were followed-up for a minimum of 18 weeks (corresponding to 6 cycles of study treatment).
Outcomes. The primary study endpoint was the overall response rate (ORR) based on the best overall response as defined by RECIST criteria v. 1.1 (without confirmation). The best overall response rate (BORR) was estimated by the ratio of patients who had a complete response (CR) or partial response (PR) and the number of subjects in the intention-to-treat (ITT) population. The number of subjects with at least one post-baseline activity assessment was used as denominator in the per-protocol (PP) analysis in supportive analysis. The secondary efficacy variables were second-line progression-free survival (PFS), defined as the time from study enrollment to disease progression or death while on second-line treatment, and overall survival (OS) from enrollment to death from any cause, Clinical Benefit Rate (CBR) estimated by the ratio of patients who had a CR, PR or stable disease (SD) for ≥24 weeks and the number of subjects in the ITT population, duration of response (DoR), safety and tolerability and Quality of Life (QoL). Second-line PFS and OS were estimated using the Kaplan Meier method. QoL was analyzed using a linear mixed model (random intercept only with time in months treated as continuous predictor) using all the available QoL assessments for each patient in the ITT population. Only data that were collected within the cutoff date (8, November 2017) were included in the present analyses.
Clinical examinations were carried out as clinically indicated before starting each cycle. Safety was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0). All grade 3–5 adverse events and serious adverse events (any grade) were recorded at every study visit. All laboratory assessments were done locally according to local standards. All patients remained in the study with continued follow-up for OS, except those who withdrew consent, were lost to follow-up, or were removed from the study by the investigator (e.g., because of another illness, an adverse event, treatment failure after a prescribed procedure, protocol violation, cure, or due to administrative reasons). Patient-reported outcomes were assessed with the Functional Assessment of Cancer Therapy–Breast questionnaire (FACT-B).