Second Line ERIbulin Followed by CApecitabine or the Reverse Sequence in HER2-negative Metastatic Breast Cancer Patients

GIM22-ERICA is a clinical trial investigating the efficacy of two different strategies in HER2 negative MBC treatment. The study will include MBC patients with histologically documented HER2 negative disease, who have progressed to one prior regimen for metastatic disease and are eligible for a second-line chemotherapy with either eribulin or capecitabine.

This study design should answer to different questions:

* What is the correct placement of Eribulin in the context of a long term treatment strategy?
* Is an early use of Eribulin the best approach for MBC pts treatment?
* May early use of Eribulin impact on subsequent treatment outcomes?

The correlated biomarkers analysis, evaluating angiogenic, epithelial and mesenchymal markers should confirm the results observed in preclinical studies ad support the clinical findings. Liquid biopsies and ctDNA evaluation could help to monitor the course of the disease and to identify novel biomarkers of drug resistance.

Patients who are considered eligible for the study treatment, will be randomly allocated within the two study arms.

ARM A:

* Second line Eribulin 1.23 mg/m2 i.v. on day 1, 8 every 21 days
* third line Capecitabine 1250 mg/m2 orally twice per day on days 1 to 14 every 21 days

ARM B:

* Second line Capecitabine 1250 mg/m2 orally twice per day on days 1 to 14 every 21 days
* Third line Eribulin 1.23 mg/m2 i.v. on day 1, 8 every 21 days

Study treatment will be continued until disease progression, death, unacceptable toxicity, Investigator's decision or patient refusal of further treatment.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent (both for clinical and blood biomarker study)
* Histological diagnosis of HER2 negative MBC
* Females ≥ 18 years
* Measurable disease (according RECIST criteria version 1.1)
* Prior Anthracyclines and Taxanes in either (neo-) adjuvant or metastatic setting, unless the patient was not suitable for one of these treatments
* 1 prior cytotoxic regimen for advanced or MBC (not including adjuvant or neo-adjuvant therapy). Patients with no prior cytotoxic regimens for advanced or metastatic disease will only be allowed if they relapsed during or within 6 months of (neo-) adjuvant cytotoxic therapy that included anathracyclines and/or taxanes (see prior criteria);
* Prior hormonotherapy and Cyclines inhibitors are allowed, so as indicated in the international guidelines for the management of hormone positive breast cancer (ER and/or PR positive);
* ECOG Performance Status ≤ 2
* Absence of angina or heart failure or infarction within 12 months from inclusion
* Adequate bone marrow and organ function as follows (haemoglobin ≥9.0 g/dl; absolute neutrophil count ≥ 1.5x103/mm3; plateled count ≥ 100x103/mm3; bilirubin levels ≤ 1.5 times Upper Limits of Normal
* biliary stenting is allowed to resolve obstruction - Serum Transaminase level ≤ 2.5 times ULN; serum creatinine ≤ 1.5 times ULN;
* Life expectancy of at least 12 weeks;
* If women of childbearing potential (WOCBP) age: effective contraceptive measures must be used during the study treatment period and up to 3 months after the last dose of study drug.

Exclusion Criteria:

* Unability to give informed consent
* Absence of measurable disease
* Concurrent active malignancies (except of in situ carcinoma of the cervix and inactive non-melanoma skin cancer)
* Current active infection;
* Serious pre-existing medical conditions or serious concomitant diseases;
* systemic disorders that would compromise the safety of the patient or her ability to complete the study, at the discretion of the investigator (for example, unstable angina pectoris, or a clinically significant history of cardiac disease or uncontrolled diabetes mellitus);
* Known immunodeficiency virus infection;
* Pregnant or breastfeeding women
* Unable to undergo medical test for geographical, social or psychological reason;
* Active or symptomatic brain metastases;
* Known complete Dihydropyrimidine dehydrogenase (DPD) deficiency (phenotype and/or genotype testing, according to applicable national guidelines, prior to the initiation of treatment with Capecitabine is recommended)
* Recent or concomitant treatment with brivudine (there must be at least a 4-week waiting period between end of treatment with brivudine and start of capecitabine therapy).