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

Overview[ - collapse ][ - ]

Purpose	Solvent-based taxanes (paclitaxel, docetaxel) cause severe toxicities not only by the active agents itself but also by the solvents like cremophor. Nab-paclitaxel (Abraxane®) is a solvent-free formulation of paclitaxel encapsulated in albumin. It does not require premedication with corticosteroids or antihistamines to prevent the risk of solvent-mediated hypersensitivity reactions. This new formulation improves safety profile, allows higher dosing with shorter infusion duration, and produces higher tumor drug concentration. As neoadjuvant treatment does not only allow to compare competing treatment approaches with a very high quality (homogenous treatment population, precise assessment of response by histological assessment), but also to identify predictive markers, this trial will compare weekly nab-paclitaxel followed by AC or EC or FEC before surgery with solvent-based paclitaxel followed by Adriamycin,Cyclophosphamide (AC) or Epirubicin,Cyclophosphamide (EC) or Fluorouracil,Epirubicin,Cyclophosphamide (FEC) before surgery. In the study several Immunohistochemistry (IHC) and molecular assays will be performed before and during the period of chemotherapy administration and at surgery with the goal of defining a marker of efficacy to be later validated in a larger adjuvant setting.
Condition	Breast Cancer
Intervention	Drug: Abraxane Drug: Paclitaxel Drug: Adriamycin or epirubicin and Cyclophosphamide (AC or EC) or Fluorouracil, epirubicin and Cyclophosphamide (FEC)
Phase	Phase 3
Sponsor	Fondazione Michelangelo
Responsible Party	Fondazione Michelangelo
ClinicalTrials.gov Identifier	NCT01822314
First Received	March 25, 2013
Last Updated	February 20, 2014
Last verified	February 2014

Tracking Information[ + expand ][ + ]

First Received Date	March 25, 2013
Last Updated Date	February 20, 2014
Start Date	April 2013
Estimated Primary Completion Date	October 2025
Current Primary Outcome Measures	pathologic Complete Response (pCR) [Time Frame: At the time of surgery: 40 months after the randomization of the first patient] [Designated as safety issue: No]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.
Current Secondary Outcome Measures	clinical Overall Response (cOR) [Time Frame: At the time of surgery: 40 months after the randomization of the first patient] [Designated as safety issue: No]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 Event Free Survival (EFS) [Time Frame: 5 years after the first patient in and 10 years after randomization of last patient in] [Designated as safety issue: No]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 Distant Event Free Survival (DEFS) [Time Frame: 5 years after the first patient in and 10 years after randomization of last patient in] [Designated as safety issue: No]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 Local Event Free Survival [Time Frame: 5 years after the first patient in and 10 years after randomization of last patient in] [Designated as safety issue: No]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 Regional Event Free Survival [Time Frame: 5 years after the first patient in and 10 years after randomization of last patient in] [Designated as safety issue: No]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. Overall Survival (OS) [Time Frame: 13 years from the date of first patient in] [Designated as safety issue: No]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. Safety and Tolerability [Time Frame: Each participant will be followed for the duration of treatment period, approximately 9 months] [Designated as safety issue: Yes]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.

Descriptive Information[ + expand ][ + ]

Brief Title	Neoadjuvant Chemotherapy With Nab-paclitaxel in Women With HER2-negative High-risk Breast Cancer
Official Title	Neoadjuvant Chemotherapy With Nab-paclitaxel in Women With HER2-negative High-risk Breast Cancer " ETNA (Evaluating Treatment With Neoadjuvant Abraxane)
Brief Summary	Solvent-based taxanes (paclitaxel, docetaxel) cause severe toxicities not only by the active agents itself but also by the solvents like cremophor. Nab-paclitaxel (Abraxane®) is a solvent-free formulation of paclitaxel encapsulated in albumin. It does not require premedication with corticosteroids or antihistamines to prevent the risk of solvent-mediated hypersensitivity reactions. This new formulation improves safety profile, allows higher dosing with shorter infusion duration, and produces higher tumor drug concentration. As neoadjuvant treatment does not only allow to compare competing treatment approaches with a very high quality (homogenous treatment population, precise assessment of response by histological assessment), but also to identify predictive markers, this trial will compare weekly nab-paclitaxel followed by AC or EC or FEC before surgery with solvent-based paclitaxel followed by Adriamycin,Cyclophosphamide (AC) or Epirubicin,Cyclophosphamide (EC) or Fluorouracil,Epirubicin,Cyclophosphamide (FEC) before surgery. In the study several Immunohistochemistry (IHC) and molecular assays will be performed before and during the period of chemotherapy administration and at surgery with the goal of defining a marker of efficacy to be later validated in a larger adjuvant setting.
Detailed Description	Not Provided
Study Type	Interventional
Study Phase	Phase 3
Study Design	Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition	Breast Cancer
Intervention	Drug: Abraxane Drug: Paclitaxel Drug: Adriamycin or epirubicin and Cyclophosphamide (AC or EC) or Fluorouracil, epirubicin and Cyclophosphamide (FEC) 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 3 weeks for 4 cycles
Study Arm (s)	Active Comparator: 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 to 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 Experimental: Abraxane Abraxane at the dosage of 125 mg/m2 over 30 minutes given week 1, 2 and 3 followed by 1 week rest to 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 3 weeks for 4 cycles

Recruitment Information[ + expand ][ + ]

Recruitment Status	Recruiting
Estimated Enrollment	632
Estimated Completion Date	October 2025
Estimated Primary Completion Date	September 2016
Eligibility Criteria	Inclusion Criteria: - Female patients aged 18 years or older - Histologically confirmed invasive unilateral breast cancer - HER2-negative disease (defined as 0-1+ by immunohistochemistry or 2+ by immunohistochemistry without HER2 amplification by either FISH, CISH, or other amplification tests done locally) - 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. Documentation of a negative pregnancy test must be available for premenopausal women with intact reproductive organs and for women less than one year after the last menstrual cycle - 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 - Any of the following abnormal baseline hematological values: 1. Absolute Neutrophil Count (ANC) < 1.5 x 10^9/L 2. Platelet count < 100 x 10^9/L 3. Hemoglobin (Hb) < 10 g/dL - Any of the following abnormal baseline laboratory tests 1. Serum total bilirubin > 1.5 x ULN (upper limit of normal) (except for patients with clearly documented Gilbert's syndrome) 2. Alanine transaminase (ALT) or aspartate transaminase (AST)> 1.25 x ULN 3. Alkaline phosphatase > 2.5 x ULN 4. Serum creatinine > 1.5 x ULN - Baseline left ventricular ejection fraction (LVEF) < 50% by echocardiography or multi-gated scintigraphic scan (MUGA)
Gender	Female
Ages	18 Years
Accepts Healthy Volunteers	No
Contacts	Contact: Pinuccia Valagussa +39 022390 pinuccia.valagussa@fondazionemichelangelo.org
Location Countries	Australia, Germany, Italy, Spain

Administrative Information[ + expand ][ + ]

NCT Number	NCT01822314
Other Study ID Numbers	FM-12-B01
Has Data Monitoring Committee	Yes
Information Provided By	Fondazione Michelangelo
Study Sponsor	Fondazione Michelangelo
Collaborators	GEICAM Breast Cancer Research Centre WA National Cancer Centre, Singapore
Investigators	Study Chair: Luca Gianni, MD San Raffaele Hospital, Milan
Verification Date	February 2014

Locations[ + expand ][ + ]

Royal Adelaide Hospital	Adelaide, South Australia, Australia, 500 Principal Investigator: Sid Selva-Nayagam, MD Not yet recruiting
Peter McCallum Cancer Centre	East Melbourne, Victoria, Australia, 8006 Principal Investigator: David Speakman, MD Not yet recruiting
Eastern Health Breast Cancer Research Maroondah Breast Clinic	Ringwood East, Victoria, Australia, 3135 Principal Investigator: Jacqui Chirgwin, MD Not yet recruiting
Mount Hospital - Breast Clinical Trials Unit	Perth, Western Australia, Australia, 6000 Principal Investigator: Arlene Chan, MD Recruiting
Royal Perth Hospital	Perth, Western Australia, Australia, 6000 Principal Investigator: Andrew Redfern, MD Recruiting
Niels-Stensen Kliniken Franzinkus-Hospital Harderberg	Hardenberg, Harderberg, Germany Principal Investigator: Albert von der Assen, MD Not yet recruiting
Universitätsklinikum Aachen Frauenklinik für Gynäkologie und Geburtsmedizin	Aachen, Germany, 52074 Principal Investigator: Dirk Bauerschlag, MD Not yet recruiting
Klinikum Augsburg International Patient Service	Augsburg, Germany, 86156 Principal Investigator: Arthur Wischnik, MD Recruiting
Frauenarzt-Zentrum-Zehlendorf	Berlin, Germany, 14169 Principal Investigator: Gerd Graffunder, MD Not yet recruiting
Augusta-Kranken-Anstalt gGmbH Klinik für Hämatologie, Onkologie & Palliativmedizin	Bochum, Germany, 44791 Principal Investigator: Dirk Behringer, MD Recruiting
Universitätsklinikum Erlangen - Frauenklinik - Poliklinik	Erlangen, Germany, 91054 Principal Investigator: Michael Patrick Lux, MD Not yet recruiting
Bethanien-Krankenhaus Onkologisches Zentrum	Frankfurt, Germany, 60389 Principal Investigator: Hans Tesch, MD Recruiting
Agaplesion Markus Hospital - Frankfurt	Frankfurt, Germany, 60389 Principal Investigator: Marc Thill, MD Recruiting
Mammazentrum - Hamburg am Krankenhaus Jerusalem	Hamburg, Germany, 20357 Principal Investigator: Pia Wülfing, MD Not yet recruiting
Gynäkologisch-Onkologische Praxis	Hannover, Germany, 30177 Principal Investigator: Hans Joachim Lück, MD Recruiting
St.Elisabeth-Krankenhaus Brustzentrum	Köln, Germany, 50935 Principal Investigator: Giese Helling, MD Recruiting
Interdisciplinary Oncology Center	Munich, Germany, 80336 Principal Investigator: Wolfang Eiermann, MD Not yet recruiting
Praxis Gynäkologie Arabella	Munich, Germany, 81925 Principal Investigator: Anita Prechtl, MD Not yet recruiting
Onkologische Schwerpunktpraxis	Speyer, Germany, 67346 Principal Investigator: Judith Franz-Werner, MD Recruiting
Cliniche Gavazzeni - Humanitas Gavazzeni	Bergamo, BG, Italy, 24125 Principal Investigator: Pier Mario Salvini, MD Not yet recruiting
Policlinico Sant'Orsola Malpighi	Bologna, BO, Italy, 40138 Principal Investigator: Claudio Zamagni, MD Recruiting
IST San Martino	Genova, GE, Italy, 16132 Principal Investigator: Lucia Del Mastro, MD Recruiting
A.O. San Gerardo	Monza, MB, Italy, 20050 Principal Investigator: Paolo Bidoli, MD Recruiting
A.O. Ospedale Civile di Legnano	Legnano, MI, Italy, 20025 Principal Investigator: Sergio Fava, MD Recruiting
A.O. Ospedale Luigi Sacco	Milano, MI, Italy, 20160 Principal Investigator: Elena Piazza, MD Not yet recruiting
Fondazione IRCCS Istituto nazionale dei tumori	Milano, MI, Italy, 20133 Principal Investigator: Angela Moliterni, MD Recruiting
A.O. Ospedale Niguarda Ca' Granda	Milano, MI, Italy, 20162 Principal Investigator: Salvatore Siena, MD Recruiting
Ospedale San Raffaele	Milano, MI, Italy, 20132 Principal Investigator: Luca Gianni, MD Recruiting
ULSS 15 Alta Padovana	Camposampiero, PD, Italy, 35012 Principal Investigator: Fernando Gaion, MD Not yet recruiting
Fondazione IRCCS Policlinico San Matteo	Pavia, PV, Italy, 27100 Principal Investigator: Paolo Pedrazzoli, MD Recruiting
Fondazione Salvatore Maugeri	Pavia, PV, Italy, 27100 Principal Investigator: Lorenzo Pavesi, MD Not yet recruiting
Arcispedale Santa Maria Nuova	Reggio Emilia, RE, Italy, 42123 Principal Investigator: Corrado Boni, MD Recruiting
Università Istituto di Clinica Medica	Sassari, SS, Italy, 07100 Principal Investigator: Maria Giuseppina Sarobbo, MD Not yet recruiting
Institute for Cancer Research and treatment	Candiolo, TO, Italy, 10060 Principal Investigator: Filippo Montemurro, MD Not yet recruiting
Ospedale Santa Maria della Misericordia	Udine, UD, Italy, 33100 Principal Investigator: Mauro Mansutti, MD Recruiting
A.O. Ospedale di Circolo	Busto Arsizio, VA, Italy, 21052 Principal Investigator: Marco Bregni, MD Not yet recruiting
Presidio Ospedaliero di Saronno	Saronno, VA, Italy, 21047 Principal Investigator: Claudio Verusio, MD Not yet recruiting
ULSS n. 13 - Presidi ospedalieri di Mirano	Mirano, VE, Italy, 30035 Principal Investigator: Mario Bari, MD Recruiting
Azienda ULSS 6 di Vicenza	Vicenza, VI, Italy, 36100 Principal Investigator: Laura Merlini, MD Not yet recruiting
Miguel Servet University Hospital	Zaragoza, Aragon, Spain, 50009 Principal Investigator: Antonio Anton, MD Recruiting
Hospital Clinico Lozano Blesa	Zaragoza, Aragon, Spain, 50009 Principal Investigator: Raquel Andrés, MD Recruiting
Hospital Son Llàtzer Palma de Mallorca	Palma de Mallorca, Baleares, Spain, 2002 Principal Investigator: Isabel Garau, MD Recruiting
Corporacio Sanitaria Parc Tauli	Sabadell, Barcelona, Spain, 08208 Principal Investigator: Miguel Angel Segui Palmer, MD Recruiting
Consorci Sanitari de Terrassa	Terrassa, Barcelona, Spain, 08227 Principal Investigator: Angels Arcusa Lanza, MD Recruiting
Hospital Universitario Fundacion Alcorcón	Alcorcón, Madrid, Spain, 28922 Principal Investigator: Carlos Jara Sánchez, MD Recruiting
Hospital Universitario de Canarias	La Laguna, Tenerife, Spain, 38320 Principal Investigator: Norberto Batista, MD Recruiting
Centro Oncologico de Galicia	A Coruña, Spain, 15009 Principal Investigator: Manuel Ramos, MD Recruiting
Hospital General Universitario de Alicante	Alicante, Spain, 03010 Principal Investigator: Josè Ponce, MD Recruiting
Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol	Badalona, Spain, 08916 Principal Investigator: Beatriz Cirauqui, MD Recruiting
Hospital del Mar	Barcelona, Spain, 08003 Principal Investigator: Ignasl Tusquets, MD Recruiting
Hospital Clinic i Provencial	Barcelona, Spain, 08036 Principal Investigator: Montserrat Munoz, MD Not yet recruiting
Hospital San Pedro de Alcantara	Caceres, Spain, 10003 Principal Investigator: Santiago Gonzalez, MD Recruiting
Hospital Universitario Reina Sofía	Córdoba, Spain, 14004 Principal Investigator: Juan de la Haba-Rodriguez, MD Recruiting
Onkologikoa	Donostia, Spain, 20014 Principal Investigator: Arrate Plazaola, MD Recruiting
Complejo Hospitalario de Jaen	Jaen, Spain, 23007 Principal Investigator: Pedro Sanchez Rovira, MD Recruiting
Hospital Teresa Herrera (Chuac)	La Coruna, Spain Principal Investigator: Lourdes Calvo, MD Recruiting
Hospital Universitari Arnau de Vilanove de Lleida	Lleida, Spain, 25198 Principal Investigator: Serafin Morales Murillo, MD Recruiting
Gregorio Maraňón Hospital	Madrid, Spain, 28009 Principal Investigator: Miguel Martin Jiménez, MD Recruiting
MD Anderson Cancer Center Madrid	Madrid, Spain Principal Investigator: Antonio Gonzalez Martin, MD Recruiting
Hospital La Paz	Madrid, Spain, 28046 Principal Investigator: Beatriz Castelo, MD Recruiting
J.M. Morales Meseguer, Universitary Hospital Marques in los Velez	Murcia, Spain, 30080 Principal Investigator: Elena Garcia Martinez, MD Recruiting
Hospital Clinico Universitario de Salamanca	Salamanca, Spain, 37007 Principal Investigator: Cesar A. Rodriguez, Md Not yet recruiting
Hospital Universitario Donostia	San Sebastián, Spain, 20080 Principal Investigator: Isabel Alvarez, MD Recruiting
Hospital Universitario Virgen Macarena	Sevilla, Spain, 41071 Principal Investigator: Luis de la Cruz Merino, MD Not yet recruiting
Hospital Virgen del Rocio	Sevilla, Spain, 41013 Principal Investigator: Manuel Ruiz Borrego, MD Recruiting
Hospital Virgen de la Salud	Toledo, Spain Principal Investigator: José L. Chacón, MD Not yet recruiting
Instituto Valenciano Oncologia	Valencia, Spain, 46009 Principal Investigator: Angel Guerrero, MD Recruiting
Hospital Clinico Universita Valencia	Valencia, Spain Principal Investigator: Begoña Bermejo, MD Recruiting
Hospital Nuestra Señora de Sonsoles	Ávila, Spain, 05004 Principal Investigator: José E. Alés-Martinez, MD Recruiting

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

Overview[ - collapse ][ - ]

Tracking Information[ + expand ][ + ]

Descriptive Information[ + expand ][ + ]

Recruitment Information[ + expand ][ + ]

Administrative Information[ + expand ][ + ]

Locations[ + expand ][ + ]