Neoadjuvant Chemotherapy With Nab-paclitaxel in Women With HER2-negative High-risk Breast Cancer

Breast Cancer Clinical Trial

— ETNA  

Official title:

Neoadjuvant Chemotherapy With Nab-paclitaxel in Women With HER2-negative High-risk Breast Cancer " ETNA (Evaluating Treatment With Neoadjuvant Abraxane)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01822314
• Other study ID #: FM-12-B01
• Secondary ID: 2012-003481-41
• Status: Completed
• Phase: Phase 3
• Start date: April 2013
• Est. completion date: March 2023

Study information

• Verified date: March 2024
• Source: Fondazione Michelangelo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the efficacy of neoadjuvant weekly nab-paclitaxel followed by Adriamycin, Cyclophosphamide (AC) or Epirubicin, Cyclophosphamide (EC) or Fluorouracil,Epirubicin,Cyclophosphamide (FEC)compared with neoadjuvant weekly solvent-based paclitaxel followed by AC or EC or FEC in terms of rate of pathological complete remissions at surgery.

Description:

In this study, eligible and consenting patients will be randomized to receive either 4 cycles of weekly abraxane (nab-paclitaxel) followed by 4 cycles of an anthracycline-containing regimen or 4 cycles of weekly paclitaxel followed by 4 cycles of an anthracycline-containing regimen.The anthracycline regimen (AC, EC or FEC) will be chosen by the investigator at the participating sites.

Before randomization patients will be stratified according to Disease stage [operable (tumor stage: T2N0-1; T3N0) and locally advanced (T3N1;T4, any N2-3)] and Tumor subtype [luminal B intermediate (HER2 negative, ER or PGR positive, Ki67 from 14% to 20%) vs luminal B high (HER2 negative, ER or PGR positive, Ki67 >20%) vs triple negative tumors (HER2 negative, ER negative and PgR negative, Ki67 any value)]. Tumor subtype will be confirmed at two selected referral laboratories.

Neoadjuvant chemotherapy will be followed by definite surgery and irradiation as per international and local guidelines.

During neoadjuvant chemotherapy patients will be assessed for safety and efficacy as detailed in the protocol.

After definite surgery patients will be followed for approximately 10 years according to local procedures

Recruitment information / eligibility

• Status: Completed
• Enrollment: 632
• Est. completion date: March 2023
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Female patients aged 18 years or older

• Histologically confirmed invasive unilateral breast cancer

• HER2-negative disease

• Known hormone receptor status (estrogen receptor [ER], progesterone receptor [PgR]), tumor grade and, if institutional standard permits, known Ki67 value

• Available paraffin-embedded tumor block taken at diagnostic biopsy for central confirmation of HER2 eligibility, hormone receptor status, Ki67 value and biomarker evaluation is mandatory

• One of the following clinical stages:

• T2, T3, T4 disease, triple negative (HER2, ER, PgR)

• T2, T3, T4 disease, ER or PgR positive and moderately differentiated or poorly differentiated tumor grade (G II-III)

• ECOG performance status 0 or 1

• Written informed consent to participate in the trial (approved by the Institutional Review Board [IRB]/ Independent Ethics Committee [IEC]) obtained prior to any study specific screening procedures

• Willing and able to comply with the protocol

Exclusion Criteria:

• Synchronous contralateral breast cancer or presence of metastatic disease (M1). Exception: contralateral insitu ductal cancer

• Surgical axillary staging procedure prior to study entry. Exceptions: 1) Fine needle aspiration (FNA) of an axillary node is permitted for any patient, and 2) although not recommended, a pre-neoadjuvant therapy sentinel lymph node biopsy for patients with clinically negative axillary nodes is permitted

• Pregnant or lactating women.

• Women with childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception, for example abstinence, an intra-uterine device, or double barrier method of contraception

• Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry

• Previous investigational treatment for any condition within 4 weeks of randomization date

• Patients on therapy with a strong CYP3A4 inhibitor and on therapy with Warfarin (Coumadin)

• Previous or concomitant malignancy of any other type that could affect compliance with the protocol or interpretation of results. Patients with curatively treated basal cell carcinoma of the skin or in situ cervix cancer are generally eligible.

• Pre-existing motor or sensory neuropathy of grade > 1 for any reason

• Patients with a history of hypersensitivity due to drugs containing polyoxyethylene castor oil (Cremophor EL) (e.g., ciclosporin), or hardened castor oil (e.g., vitamin preparations for injection, etc.)

• Other serious illness or medical condition including: history of documented congestive cardiac failure; angina pectoris requiring anti-anginal medication; evidence of transmural infarction on ECG; poorly controlled hypertension (e.g. systolic >180 mm Hg or diastolic >100 mm Hg; however, patients with hypertension which is well controlled on medication are eligible); clinically significant valvular heart disease; high-risk uncontrolled arrhythmias

• Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or adversely affecting compliance with study drugs

• Serious uncontrolled infections (bacterial or viral) or poorly controlled diabetes mellitus

• Hematology and biochemistry tests within normla limits

• Baseline left ventricular ejection fraction (LVEF) < 50% by echocardiography or multi-gated scintigraphic scan (MUGA)

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Abraxane
Abraxane at the dosage of 125 mg/m2 will be delivered over 30 minutes on week 1, 2 and 3 followed by 1 week rest. week rest and will be repeated for 4 cycles followed by AC or EC (adriamycin or epirubicin and cyclophosphamide) on day 1 every 3 weeks for 4 cycles or FEC (fluorouracil, epirubicin, and cyclophosphamide) on day 1 every three weeks for 4 cycles
• Paclitaxel
Paclitaxel at the dosage of 90 mg/m2 diluted in 250 mL of water for injection (WFI) over 1 hour given week 1, 2 and 3 followed by 1 week rest and will be repeated for 4 cycles followed by AC or EC (adriamycin or epirubicin and cyclophosphamide) on day 1 every 3 weeks for 4 cycles or FEC (fluorouracil, epirubicin, and cyclophosphamide) on day 1 every three weeks for 4 cycles

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Peter MacCallum Cancer Centre Department of Surgical Oncology	East Melbourne	Victoria
Australia	Peter McCallum Cancer Centre	East Melbourne	Victoria
Australia	Mount Hospital - Breast Clinical Trials Unit	Perth	Western Australia
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Eastern Health Breast Cancer Research - Maroondah Breast Clinic	Ringwood East	Victoria
Australia	Eastern Health Breast Cancer Research Maroondah Breast Clinic	Ringwood East	Victoria
Germany	Klinikum Augsburg International Patient Service	Augsburg
Germany	Frauenarzt-Zentrum-Zehlendorf	Berlin
Germany	Augusta-Kranken-Anstalt gGmbH Klinik für Hämatologie, Onkologie & Palliativmedizin	Bochum
Germany	Universitätsklinikum Erlangen - Frauenklinik - Poliklinik	Erlangen
Germany	Agaplesion Markus Hospital - Frankfurt	Frankfurt
Germany	Bethanien-Krankenhaus Onkologisches Zentrum	Frankfurt
Germany	Mammazentrum - Hamburg am Krankenhaus Jerusalem	Hamburg
Germany	Gynäkologisch-Onkologische Praxis	Hannover
Germany	St.Elisabeth-Krankenhaus Brustzentrum	Köln
Germany	Interdisciplinary Oncology Center	Munich
Germany	Praxis Gynäkologie Arabella	Munich
Germany	Onkologische Schwerpunktpraxis	Speyer
Italy	Cliniche Gavazzeni - Humanitas Gavazzeni	Bergamo	BG
Italy	Policlinico Sant'Orsola Malpighi	Bologna	BO
Italy	ULSS 15 Alta Padovana	Camposampiero	PD
Italy	Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna	Cona	Ferrara
Italy	IST San Martino	Genova	GE
Italy	A.O. Ospedale Civile di Legnano	Legnano	MI
Italy	A.O. Ospedale Luigi Sacco	Milano	MI
Italy	A.O. Ospedale Niguarda Ca' Granda	Milano	MI
Italy	Fondazione IRCCS Istituto nazionale dei tumori	Milano	MI
Italy	Ospedale San Raffaele	Milano	MI
Italy	A.O. San Gerardo	Monza	MB
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia	PV
Italy	Arcispedale Santa Maria Nuova	Reggio Emilia	RE
Italy	Ospedale Santa Maria della Misericordia	Udine	UD
Italy	Azienda ULSS 6 di Vicenza	Vicenza	VI
Russian Federation	NN Petrov Research Institute of Oncology	St. Petersburg
Singapore	National Cancer Centre Singapore	Singapore
Spain	Centro Oncologico de Galicia	A Coruña
Spain	Hospital Universitario Fundacion Alcorcón	Alcorcón	Madrid
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Nuestra Señora de Sonsoles	Ávila
Spain	Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol	Badalona
Spain	Hospital Clinic i Provencial	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital San Pedro de Alcantara	Caceres
Spain	Hospital Universitario Reina Sofía	Córdoba
Spain	Onkologikoa	Donostia
Spain	Complejo Hospitalario de Jaen	Jaen
Spain	Hospital Teresa Herrera (Chuac)	La Coruna
Spain	Hospital Universitario de Canarias	La Laguna	Tenerife
Spain	Hospital Universitari Arnau de Vilanove de Lleida	Lleida
Spain	Gregorio Maranón Hospital	Madrid
Spain	Hospital La Paz	Madrid
Spain	MD Anderson Cancer Center Madrid	Madrid
Spain	J.M. Morales Meseguer, Universitary Hospital Marques in los Velez	Murcia
Spain	Hospital Son Llàtzer Palma de Mallorca	Palma de Mallorca	Baleares
Spain	Corporacio Sanitaria Parc Tauli	Sabadell	Barcelona
Spain	Hospital Clinico Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Donostia	San Sebastián
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Virgen del Rocio	Sevilla
Spain	Consorci Sanitari de Terrassa	Terrassa	Barcelona
Spain	Hospital Virgen de la Salud	Toledo
Spain	Hospital Clinico Universita Valencia	Valencia
Spain	Instituto Valenciano Oncologia	Valencia
Spain	Hospital Clinico Lozano Blesa	Zaragoza	Aragon
Spain	Miguel Servet University Hospital	Zaragoza	Aragon

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione Michelangelo

Countries where clinical trial is conducted

Australia,  Germany,  Italy,  Russian Federation,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	pathologic Complete Response (pCR)	To compare the rate of pathologic Complete Response (pCR, absence of invasive disease in breast and nodes (ypT0/ypTis, ypN0)) for abraxane (Abraxane®, abraxane) vs paclitaxel.	At the time of surgery: 40 months after the randomization of the first patient
Secondary	clinical Overall Response (cOR)	To compare the rate of clinical overall response (cOR) after the first 4 cycles of abraxane vs paclitaxel and to compare the rate of cOR after the entire preoperative chemotherapy (i.e. before surgery) in the study arms of abraxane vs paclitaxel	At the time of surgery: 40 months after the randomization of the first patient
Secondary	Event Free Survival (EFS)	To compare the Event Free Survival (EFS, i.e. disease progression while on primary therapy or disease recurrence after surgery) in the study arms of abraxane vs paclitaxel	5 years after the first patient in and 10 years after randomization of last patient in
Secondary	Distant Event Free Survival (DEFS)	The distant event free survival (DEFS) is defined as the time from randomization to the first date of distant metastasis while on primary therapy or distant recurrence after surgery or death due to any cause. Patients who terminate the study without evidence of any of the above events will be censored at the date of their last follow-up tumor assessment	5 years after the first patient in and 10 years after randomization of last patient in
Secondary	Local Event Free Survival	The local event free survival (LEFS) is defined as the time from randomization to the first date of local progression while on primary therapy or local recurrence after surgery. Rules for censoring and methods of analysis will be the same as defined for EFS	5 years after the first patient in and 10 years after randomization of last patient in
Secondary	Regional Event Free Survival	The regional event free survival (REFS) is defined as the time from randomization to the first date of regional progression while on primary therapy or regional recurrence after surgery. Rules for censoring and methods of analysis will be the same as defined for EFS.	5 years after the first patient in and 10 years after randomization of last patient in
Secondary	Overall Survival (OS)	The overall survival (OS) is defined as the time from randomization to the date of death. Patients alive at the end of study will be censored at their last contact date.	13 years from the date of first patient in
Secondary	Safety and Tolerability	Patients will be assessed for adverse events by clinical examination, questioning for symptoms of toxicity, laboratory assessments, vital signs, ECG and LVEF.; Neurological toxicity and other toxicities will be assessed throughout the study according the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0.	Each participant will be followed for the duration of treatment period, approximately 9 months