Pharmacogenomic Study of Neoadjuvant Eribulin for HER2 Non-overexpressing Breast Cancer (NeoEribulin)

• Rate of pCRB, defined as the complete absence of invasive carcinoma in the breast on histological examination at the time of definitive surgery, according to the NSABP guidelines. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Rate of pCRBL, defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination at the time of definitive surgery. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Clinical and radiological ORR, defined by RECIST 1.1 [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Correlation of mRNA expression in breast tumors with clinical and radiological ORR at different time points during the neoadjuvant treatment with eribulin. [ Time Frame: Up to 21 weeks ] [ Designated as safety issue: No ]
• Rate of pCRB according to breast cancer subtype: Luminal A, Luminal B, Basal-like, HER2-enriched and Claudin-low. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Rate of pCRB according to breast cancer subtype determined by immunohistochemistry (following the 2011 St. Gallen definitions): Luminal A, Luminal B, and TNBC. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Proportion of patients able to have breast conservation surgery after being treated with eribulin as neoadjuvant therapy. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• The correlation between alternations in tubulin isotype expression and mutational status in pre-treatment samples with efficacy parameters, such as pCRB, ORR and BOR. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• The correlation between exome or genome sequencing data from pre-treatment samples with pCRB after neoadjuvant treatment with eribulin. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Changes in gene expression and gene mutational status between the pre-treatment samples and samples after treatment. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Number of participants with AEs and serious AEs (assessed by CTCAE v.4) [ Time Frame: Up to 21 weeks ] [ Designated as safety issue: Yes ]
• Percentage of patients who had neutropenia Grade 3-4 [ Time Frame: Up to 21 weeks ] [ Designated as safety issue: Yes ]
• Percentage of subjects with neuropathy [ Time Frame: Up to 21 weeks ] [ Designated as safety issue: Yes ]
• Incidence of dose reductions and/or dose delays due to treatment toxicity [ Time Frame: Up to 71 days ] [ Designated as safety issue: Yes ]
• Analysis of the expression of mRNA from breast tumors [ Time Frame: At screening ] [ Designated as safety issue: No ]
• Analysis of the expression of mRNA from breast tumors [ Time Frame: At 21 days ] [ Designated as safety issue: No ]
• Analysis of the expression of mRNA from breast tumors [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Correlation of mRNA expression in breast tumors after 21 days of neoadjuvant treatment and at surgery with pCRB. [ Time Frame: At the time of definitive surgery ] [ Designated as safety issue: No ]
• Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin. [ Time Frame: At screening ] [ Designated as safety issue: No ]
• Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin. [ Time Frame: At 21 days ] [ Designated as safety issue: No ]
• Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin. [ Time Frame: At time of definitive surgery ] [ Designated as safety issue: No ]
• Specificity of the gene expression analysis of samples to predict clinical response to eribulin. [ Time Frame: At screening ] [ Designated as safety issue: No ]
• Specificity of the gene expression analysis of samples to predict clinical response to eribulin. [ Time Frame: At 21 days ] [ Designated as safety issue: No ]
• Specificity of the gene expression analysis of samples to predict clinical response to eribulin. [ Time Frame: At time of definitive surgery ] [ Designated as safety issue: No ]

This is a prospective, non-randomized, open-label, multicenter, single-arm exploratory pharmacogenomic study of single agent eribulin as neoadjuvant therapy in patients with operable Stage III HER2 non-overexpressing breast cancer.

Inclusion Criteria:

• Written informed consent, specifically highlighting the molecular characterization of tumor and genomic samples
• Age ≥18 years

• Histologically confirmed invasive breast carcinoma, with all of the following characteristics:

  • Primary tumor ≥2cm in largest diameter (cT1-3)
  • cN0-1
  • No evidence of distant metastasis (M0)
• Breast cancer (BC) eligible for primary surgery
• Available pre-treatment core (Tru-cut) biopsy or possibility of performing one

• HER2-negative BC (as per local assessment), defined as either of the following:

  • 0-1+ expression by IHC
  • 2+ expression by IHC and in situ hybridization (FISH/CISH) without HER2 gene amplification (<4 HER2 gene copies per nucleus, or a FISH ratio [HER2 gene copies to Cr17 signals] of <1.8)
  • Is situ hybridization (FISH/CISH) without HER2 gene amplification, independently of IHC
• Known hormone receptor (ER/PgR) status (as per local assessment) or the possibility of performing the tests
• Known percentage of hormone receptor (ER/PgR) and Ki67-positive tumor cells (as per local assessment), or possibility of performing the tests
• In the case of a multifocal tumor, the largest lesion must be ≥2 cm and designated the "target" lesion for all subsequent tumor evaluations and HER2-negative status must be documented in all the tumor foci
• ECOG performance status of 0 or 1

• Laboratory values as follows:

  • Absolute neutrophil count (ANC) ≥1.5 x 109/L
  • Platelets count ≥100 x 109/L
  • Hemoglobin ≥9 g/dL
  • Serum bilirubin ≤1.5 time the upper limit of normal (ULN)
  • Alanine aminotransferase and aspartate aminotransferase (AST) ≤2.5 x ULN
  • Alkaline phosphatase ≤2.5 x ULN
  • Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥60 mL/m
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol
• Availability of genomic DNA (via whole blood)

Exclusion Criteria:

• Any prior treatment for primary invasive BC
• Metastatic, locally advanced or inflammatory (i.e., Stage III-IV) BC
• Bilateral invasive BC
• Multicentric BC, defined as the presence of two or more foci of cancer in different quadrants of the same breast
• Pre-existing peripheral neuropathy of any grade
• Uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg)
• Clinically significant (i.e., active) cardiovascular disease
• Long QT syndrome
• Concomitant use of inhibitors of hepatic transport proteins such as organic anion-transporting proteins, P-glycoprotein, multidrug resistant proteins etc
• Major medical conditions that might affect study participation (e.g., uncontrolled seizure disorder, uncontrolled pulmonary, renal or hepatic dysfunction, or uncontrolled infection)
• Other primary malignant tumors within the previous 5 years, except for adequately controlled limited basal cell carcinoma of the skin or carcinoma in situ of the cervix
• Known human immunodeficiency virus(HIV) infection or other active or serious infection requiring IV antibiotics at randomization
• Pregnancy or breastfeeding women
• Women of childbearing potential(<2 years after the last menstruation) not using effective, non-hormonal means of contraception during the study and for a period of 6 months following the last administration of study drug
• Administration of any live virus vaccine within 8 weeks preceding study entry
• Use of any investigational agent within 30 days of administration of the first dose of study drug or concurrent treatment on another clinical study
• Requirement for radiation therapy concurrent with study anticancer treatment
• Known hypersensitivity to any of the study drugs or excipients
• Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator or designee