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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Phase II, Open-label, Single-arm, Exploratory Pharmacogenomic Study of Single Agent Eribulin (HALAVEN®) as Neoadjuvant Treatment for Operable Stage I-II HER2 Non-overexpressing Breast Cancer.

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Eribulin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eribulin<br>1.23 mg/m2 eribulin ready to use solution (equivalent to 1.4 mg/m2 eribulin mesilate) IV on Days 1 and 8 of every 21-day cycle, for 4 cycles. | Drug: Eribulin<br>* 1.23 mg/m2 eribulin ready to use solution (equivalent to 1.4 mg/m2 eribulin mesilate) IV on Days 1 and 8 of every 21-day cycle, for 4 cycles.<br>* Other names: Halaven(R);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of pre-treatment relative abundance of hundreds of mRNA transcripts from primary breast tumors with pCRB after neoadjuvant treatment with eribulin. | 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 | At the time of definitive surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | At the time of definitive surgery | 
| 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. |  | At the time of definitive surgery | 
| Clinical and radiological ORR, defined by RECIST 1.1 |  | At the time of definitive surgery | 
| Correlation of mRNA expression in breast tumors with clinical and radiological ORR at different time points during the neoadjuvant treatment with eribulin. |  | Up to 21 weeks | 
| Rate of pCRB according to breast cancer subtype: Luminal A, Luminal B, Basal-like, HER2-enriched and Claudin-low. |  | At the time of definitive surgery | 
| Rate of pCRB according to breast cancer subtype determined by immunohistochemistry (following the 2011 St. Gallen definitions): Luminal A, Luminal B, and TNBC. |  | At the time of definitive surgery | 
| Proportion of patients able to have breast conservation surgery after being treated with eribulin as neoadjuvant therapy. |  | At the time of definitive surgery | 
| The correlation between alternations in tubulin isotype expression and mutational status in pre-treatment samples with efficacy parameters, such as pCRB, ORR and BOR. |  | At the time of definitive surgery | 
| The correlation between exome or genome sequencing data from pre-treatment samples with pCRB after neoadjuvant treatment with eribulin. |  | At the time of definitive surgery | 
| Changes in gene expression and gene mutational status between the pre-treatment samples and samples after treatment. |  | At the time of definitive surgery | 
| Number of participants with AEs and serious AEs (assessed by CTCAE v.4) |  | Up to 21 weeks | 
| Percentage of patients who had neutropenia Grade 3-4 |  | Up to 21 weeks | 
| Percentage of subjects with neuropathy |  | Up to 21 weeks | 
| Incidence of dose reductions and/or dose delays due to treatment toxicity |  | Up to 71 days | 
| Analysis of the expression of mRNA from breast tumors |  | At screening | 
| Analysis of the expression of mRNA from breast tumors |  | At 21 days | 
| Analysis of the expression of mRNA from breast tumors |  | At the time of definitive surgery | 
| Correlation of mRNA expression in breast tumors after 21 days of neoadjuvant treatment and at surgery with pCRB. |  | At the time of definitive surgery | 
| Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin. |  | At screening | 
| Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin. |  | At 21 days | 
| Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin. |  | At time of definitive surgery | 
| Specificity of the gene expression analysis of samples to predict clinical response to eribulin. |  | At screening | 
| Specificity of the gene expression analysis of samples to predict clinical response to eribulin. |  | At 21 days | 
| Specificity of the gene expression analysis of samples to predict clinical response to eribulin. |  | At time of definitive surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast cancer, Eribulin, Neoadjuvant, PAM50, Triple-negative, Luminal A, Luminal B