Clinical trial NCT01669252: Pharmacogenomic Study of Neoadjuvant Eribulin for 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Breast cancer
Eribulin
Neoadjuvant
PAM50
Triple-negative
Luminal A
Luminal B
Lead sponsor: SOLTI Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: Eisai Inc.
First posted: 2012-08-20
Enrollment: 163
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Correlation of pre-treatment relative abundance of hundreds of mRNA transcripts from primary breast tumors with pCRB after neoadjuvant treatment with eribulin.
timeFrame: At the time of definitive surgery.
Secondary outcomes:
measure: 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.
timeFrame: At the time of definitive surgery
measure: 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.
timeFrame: At the time of definitive surgery
measure: Clinical and radiological ORR, defined by RECIST 1.1
timeFrame: At the time of definitive surgery
measure: Correlation of mRNA expression in breast tumors with clinical and radiological ORR at different time points during the neoadjuvant treatment with eribulin.
timeFrame: Up to 21 weeks
measure: Rate of pCRB according to breast cancer subtype: Luminal A, Luminal B, Basal-like, HER2-enriched and Claudin-low.
timeFrame: At the time of definitive surgery
measure: Rate of pCRB according to breast cancer subtype determined by immunohistochemistry (following the 2011 St. Gallen definitions): Luminal A, Luminal B, and TNBC.
timeFrame: At the time of definitive surgery
measure: Proportion of patients able to have breast conservation surgery after being treated with eribulin as neoadjuvant therapy.
timeFrame: At the time of definitive surgery
measure: The correlation between alternations in tubulin isotype expression and mutational status in pre-treatment samples with efficacy parameters, such as pCRB, ORR and BOR.
timeFrame: At the time of definitive surgery
measure: The correlation between exome or genome sequencing data from pre-treatment samples with pCRB after neoadjuvant treatment with eribulin.
timeFrame: At the time of definitive surgery
measure: Changes in gene expression and gene mutational status between the pre-treatment samples and samples after treatment.
timeFrame: At the time of definitive surgery
measure: Number of participants with AEs and serious AEs (assessed by CTCAE v.4)
timeFrame: Up to 21 weeks
measure: Percentage of patients who had neutropenia Grade 3-4
timeFrame: Up to 21 weeks
measure: Percentage of subjects with neuropathy
timeFrame: Up to 21 weeks
measure: Incidence of dose reductions and/or dose delays due to treatment toxicity
timeFrame: Up to 71 days
measure: Analysis of the expression of mRNA from breast tumors
timeFrame: At screening
measure: Analysis of the expression of mRNA from breast tumors
timeFrame: At 21 days
measure: Analysis of the expression of mRNA from breast tumors
timeFrame: At the time of definitive surgery
measure: Correlation of mRNA expression in breast tumors after 21 days of neoadjuvant treatment and at surgery with pCRB.
timeFrame: At the time of definitive surgery
measure: Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin.
timeFrame: At screening
measure: Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin.
timeFrame: At 21 days
measure: Sensitivity of the gene expression analysis of samples to predict clinical response to eribulin.
timeFrame: At time of definitive surgery
measure: Specificity of the gene expression analysis of samples to predict clinical response to eribulin.
timeFrame: At screening
measure: Specificity of the gene expression analysis of samples to predict clinical response to eribulin.
timeFrame: At 21 days
measure: Specificity of the gene expression analysis of samples to predict clinical response to eribulin.
timeFrame: At time of definitive surgery
Other outcomes:
Locations:
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Deggendorf
country: Germany
facility: Klinikum des Landkreises Deggendorf Frauenklinik Mammazentrum
city: Köln
country: Germany
facility: Brustzentrum im Krankenhaus Köln-Holweide Priv. Doz.
city: Munic
country: Germany
facility: Brustzentrum der Universität München
city: Rostock
country: Germany
facility: Klinikum Südstadt Rostock, Universitätsfrauenklinik und Poliklinik
city: Coimbra
country: Portugal
facility: Instituto Portugues de Oncologia de Coimbra Francisco Gentil, EPE
city: Lisboa
country: Portugal
facility: Hospital da Luz
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia de Porto Francisco Gentil, EPE
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d´Hebron
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d´Hebron
city: Castelló de la Plana
country: Spain
facility: Complejo Hospitalario de Castellón
city: Cáceres
country: Spain
facility: Complejo Hospitalario San Pedro de Alcántara
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Denia
country: Spain
facility: Hospital Marina Salud de Denia
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaén
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro de Majadahonda
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Reus
country: Spain
facility: Hospital Universitari Sant Joan de Reus
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
city: Sevilla
country: Spain
facility: Hospital Virgen de la Macarena
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Torrevieja
country: Spain
facility: Hospital de Torrevieja
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova de Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Lozano Blesa
Study officials:
affiliation: Hospital Universitario Vall d´Hebron
name: Javier Cortés, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vall d´Hebron Institut d´Oncologia
name: Aleix Prat, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.