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

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.

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Eribulin

• Study Type: Interventional
• Enrollment (Actual): 163
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Villejuif, France, 94800
    • Institut Gustave Roussy
• Germany
  • Deggendorf, Germany, 94469
    • Klinikum des Landkreises Deggendorf Frauenklinik Mammazentrum
  • Köln, Germany, 51067
    • Brustzentrum im Krankenhaus Köln-Holweide Priv. Doz.
  • Munic, Germany, 81377
    • Brustzentrum der Universität München
  • Rostock, Germany, 18059
    • Klinikum Südstadt Rostock, Universitätsfrauenklinik und Poliklinik
• Portugal
  • Coimbra, Portugal, 3001-651
    • Instituto Portugues de Oncologia de Coimbra Francisco Gentil, EPE
  • Lisboa, Portugal, 1500-650
    • Hospital Da Luz
  • Porto, Portugal, 4200-072
    • Instituto Portugues de Oncologia de Porto Francisco Gentil, EPE
• Spain
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Hospital Universitario Vall d´Hebron
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d´Hebron
  • Castelló de la Plana, Spain, 12002
    • Complejo Hospitalario de Castellón
  • Cáceres, Spain, 10003
    • Complejo Hospitalario San Pedro de Alcantara
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • Denia, Spain, 03700
    • Hospital Marina Salud de Dénia
  • Jaén, Spain, 23007
    • Complejo Hospitalario de Jaén
  • Lleida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova de Lleida
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 De Octubre
  • Madrid, Spain, 28040
    • Hospital Universitario Clinico San Carlos
  • Madrid, Spain, 28222
    • Hospital Universitario Puerta de Hierro de Majadahonda
  • Murcia, Spain, 30120
    • Hospital Universitario Virgen de la Arrixaca
  • Reus, Spain, 43201
    • Hospital Universitari Sant Joan de Reus
  • Santiago de Compostela, Spain, 15706
    • Complejo Hospitalario Universitario de Santiago
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Sevilla, Spain, 41007
    • Hospital Virgen de la Macarena
  • Torrevieja, Spain, 03186
    • Hospital de Torrevieja
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Valencia, Spain, 46015
    • Hospital Arnau de Vilanova de Valencia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Lozano Blesa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eribulin; 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; 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.; 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	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

Collaborators and Investigators

• Sponsor: SOLTI Breast Cancer Research Group
• Collaborators: Eisai Inc.
• Investigators: Principal Investigator: Javier Cortés, MD, Hospital Universitario Vall d´Hebron; Principal Investigator: Aleix Prat, MD, Vall d´Hebron Institut d´Oncologia

Publications and helpful links

General Publications

• Prat P, Llombart A, de la Peña L, Di Cosimo S, Oliveira M, Ortega V, Rubio I, Muñoz E, Harbeck N, Cortés J. NeoEribulin: A Phase II, non-randomized, open-label, single-arm, multicenter, exploratory pharmacogenomic study of single agent eribulin as neoadjuvant treatment for operable Stage I-II HER2 non-overexpressing breast cancer. Poster session presented at: 35th Annual San Antonio Breast Cancer Symposium (SABCS); 2012 December 4th-8th; San Antonio, Texas, United States.

Helpful Links

• SOLTI Breast Cancer Research Group

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: August 9, 2012
• First Submitted That Met QC Criteria: August 16, 2012
• First Posted (Estimate): August 20, 2012

Study Record Updates

• Last Update Posted (Actual): November 6, 2017
• Last Update Submitted That Met QC Criteria: October 31, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Breast cancer; Eribulin; Neoadjuvant; Triple-negative; Luminal A; PAM50; Luminal B
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: SOLTI-1007; 2012-000394-23 (EudraCT Number)