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

Overview

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.

Full Title of Study: “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.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 2015

Interventions

  • 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.

Arms, Groups and Cohorts

  • 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.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • 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
  • 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
  • Clinical and radiological ORR, defined by RECIST 1.1
    • Time Frame: 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.
    • Time Frame: Up to 21 weeks
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Number of participants with AEs and serious AEs (assessed by CTCAE v.4)
    • Time Frame: Up to 21 weeks
  • Percentage of patients who had neutropenia Grade 3-4
    • Time Frame: Up to 21 weeks
  • Percentage of subjects with neuropathy
    • Time Frame: Up to 21 weeks
  • Incidence of dose reductions and/or dose delays due to treatment toxicity
    • Time Frame: Up to 71 days
  • Analysis of the expression of mRNA from breast tumors
    • Time Frame: At screening
  • Analysis of the expression of mRNA from breast tumors
    • Time Frame: At 21 days
  • Analysis of the expression of mRNA from breast tumors
    • Time Frame: At the time of definitive surgery
  • 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
  • Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin.
    • Time Frame: At screening
  • Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin.
    • Time Frame: At 21 days
  • Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin.
    • Time Frame: At time of definitive surgery
  • Specificity of the gene expression analysis of samples to predict clinical response to eribulin.
    • Time Frame: At screening
  • Specificity of the gene expression analysis of samples to predict clinical response to eribulin.
    • Time Frame: At 21 days
  • Specificity of the gene expression analysis of samples to predict clinical response to eribulin.
    • Time Frame: At time of definitive surgery

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • SOLTI Breast Cancer Research Group
  • Collaborator
    • Eisai Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Javier Cortés, MD, Principal Investigator, Hospital Universitario Vall d´Hebron
    • Aleix Prat, MD, Principal Investigator, Vall d´Hebron Institut d´Oncologia

References

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.

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