Clinical trial NCT00381901: Trastuzumab for 6 Months or 1 Year in Treating Women With Nonmetastatic Breast Cancer That Can Be Removed By Surgery
Official title: Protocol of Herceptin Adjuvant With Reduced Exposure, a Randomised Comparison of 6 Months vs 12 Months in All Women Receiving Adjuvant Herceptin [PHARE]
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IA breast cancer
stage IB breast cancer
recurrent breast cancer
stage IIIC breast cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-09-28
Enrollment: 3400
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving trastuzumab for 6 months is as effective as giving trastuzumab for 1 year in treating patients with breast cancer.

PURPOSE: This randomized phase III trial is studying trastuzumab to see how well it works when given for 6 months compared to 12 months in treating women with nonmetastatic breast cancer that can be removed by surgery.

Detailed description: OBJECTIVES:

Primary

* Compare the disease-free survival of women with nonmetastatic, resectable breast cancer treated with adjuvant trastuzumab (Herceptin®) for 6 months vs 12 months.

Secondary

* Compare cardiotoxicity in patients receiving these regimens.
* Compare the cardiotoxicity and disease-free survival of patients receiving concurrent trastuzumab and chemotherapy vs sequential administration.
* Correlate HER-2 polymorphism with disease-free survival/cardiotoxicity in these patients.

OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to participating center, modality of adjuvant chemotherapy (concurrent vs sequential), and adjuvant hormonal therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

* Arm I (control arm, 12-month therapy): Patients continue to receive trastuzumab (Herceptin®) IV until a total of 12 months of therapy is completed in the absence of disease progression or unacceptable toxicity.
* Arm II (experimental arm, 6-month therapy): Patients continue to receive trastuzumab\* IV until a total of 6 months of therapy is completed in the absence of disease progression or unacceptable toxicity.

NOTE: \*Patients who have already finished 6 months of trastuzumab at randomization do not receive further trastuzumab.

Some patients undergo blood collection for HER-2 polymorphism analysis.

After completion of study therapy, patients are followed periodically for approximately 5 years.

PROJECTED ACCRUAL: A total of 7,000 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed adenocarcinoma of the breast
* Nonmetastatic disease

  * Positive or negative axillary nodes
  * Tumor size ≥ 10 mm
* Resectable disease
* Must have received ≥ 4 courses of chemotherapy for this disease
* A 12-month adjuvant treatment with trastuzumab (Herceptin®) has been initiated

  * Informed consent form must be signed between the third and sixth months of trastuzumab therapy
* Overexpression of HER-2 in the invasive component of the primary tumor as indicated by 1 of the following:

  * 3+ by immunohistochemistry (IHC)
  * 2+ by IHC and confirmation by fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH)
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* Female
* Menopausal status not specified
* LVEF considered favorable for continuing trastuzumab treatment as measured by echocardiography or MUGA at 2-4 months after beginning adjuvant trastuzumab
* No serious cardiac illness or medical condition precluding trastuzumab treatment, including any of the following:

  * History of documented congestive heart failure
  * High-risk uncontrolled arrhythmias
  * Angina pectoris requiring antianginal medication
  * Severe dyspnea at rest or oxygen-dependent
* No known hypersensitivity to trastuzumab, murine proteins, or any of the excipients
* Not pregnant or nursing
* No social, geographical, or psychological condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* Other prior anti-HER-2 therapy allowed
* No prior trastuzumab other than initiation of trastuzumab adjuvant therapy

Primary outcomes:
measure: Time to recurrence
Secondary outcomes:
measure: Cardiotoxicity as measured by LVEF
measure: Distant metastasis-free survival
measure: Overall survival
Other outcomes:
Locations:
city: Angers
country: France
facility: Centre Paul Papin
city: Annecy
country: France
facility: Centre Hospitalier d'Annecy
city: Antibes
country: France
facility: Centre Hospitalier La Fontonne
city: Argenteuil
country: France
facility: Centre Hospitalier Victor Dupouy
city: Aulnay Sous Bois
country: France
facility: Centre Hospital General Robert Ballanger
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Beauvais
country: France
facility: C.H.G. Beauvais
city: Besancon
country: France
facility: Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
city: Bobigny
country: France
facility: Hopital Avicenne
city: Bordeaux
country: France
facility: Institut Bergonie
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord Aquitaine
city: Bordeaux
country: France
facility: Clinique Tivoli
city: Boulogne Sur Mer
country: France
facility: Centre Hospitalier Docteur Duchenne
city: Brest
country: France
facility: C.H.U. de Brest
city: Brive
country: France
facility: Centre Hospitalier General
city: Chalon-sur-Saone
country: France
facility: Centre Hospitalier William Morey
city: Chartres
country: France
facility: Clinique Notre Dame du Bon Secours
city: Chartres
country: France
facility: Hopital Louis Pasteur
city: Clamart
country: France
facility: Hopital Antoine Beclere
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Colmar
country: France
facility: Hopital Louis Pasteur
city: Dax
country: France
facility: Centre Hospitalier de Dax
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer Georges-Francois Leclerc
city: Epinal
country: France
facility: Hopital Jean Monnet
city: Fort de France Cedex
country: France
facility: Hopital Clarac
city: Grenoble
country: France
facility: Institut Prive de Cancerologie
city: Hyeres
country: France
facility: Clinique Sainte-Marguerite
city: La Garenne Colombes
country: France
facility: Centre De Radiotherapie Charlebourg
city: La Roche Sur Yon
country: France
facility: Centre Hospitalier Departemental
city: Lagny Sur Marne
country: France
facility: Centre Hospitalier de Lagny
city: Le Chesnay
country: France
facility: Hopital Andre Mignot
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Levallois-Perret
country: France
facility: Institut d'Oncologie Hartmann
city: Libourne
country: France
facility: Hopital Robert Boulin
city: Limoges
country: France
facility: Clinique Chenieux
city: Limoges
country: France
facility: Centre Hospital Regional Universitaire de Limoges
city: Lyon
country: France
facility: Centre Medical Parot
city: Lyon
country: France
facility: Centre Leon Berard
city: Lyon
country: France
facility: Hopital Edouard Herriot - Lyon
city: Mareuil Les Meaux
country: France
facility: Centre de Radiotherapie et Oncologie Saint-Faron
city: Marseille
country: France
facility: Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
city: Metz
country: France
facility: Hopital Clinique Claude Bernard
city: Meudon La Foret
country: France
facility: Centre de Radiologie et de Traitement des Tumeurs
city: Meulan
country: France
facility: CH Meulan
city: Mont-de-Marsan
country: France
facility: Centre Hospitalier General de Mont de Marsan
city: Montelimar
country: France
facility: Centre Hospitalier de Montelimar
city: Montlucon
country: France
facility: Centre Hospitalier de Montlucon
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Montpellier
country: France
facility: Clinique Clementville
city: Mougins
country: France
facility: Centre Azureen de Cancerologie
city: Nantes-Saint-Herblain
country: France
facility: Centre Regional Rene Gauducheau
city: Nantes
country: France
facility: Centre Catherine de Sienne
city: Narbonne
country: France
facility: Clinique Les Genets
city: Neuilly sur Seine
country: France
facility: Clinique Hartmann
city: Nice
country: France
facility: Clinique Belvedere
city: Nice
country: France
facility: Clinique Saint George
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nimes
country: France
facility: C.H.U. de Nimes - Groupe Hospitals-Universitaire Caremeau
city: Nimes
country: France
facility: Clinique De Valdegour
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Paris
country: France
facility: Institut Curie Hopital
city: Paris
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: CHU Pitie-Salpetriere
city: Pau
country: France
facility: Centre Hospitalier - Pau
city: Perigueux
country: France
facility: Polyclinique Francheville
city: Perpignan
country: France
facility: Clinique Saint - Pierre
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Poissy
country: France
facility: Centre Hospitalier Intercommunal de Poissy
city: Poitiers
country: France
facility: Hopital Jean Bernard
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Roanne
country: France
facility: CHG Roanne
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Brieuc
country: France
facility: Clinique Armoricaine De Radiologie
city: Saint Priest en Jarez
country: France
facility: Institut de Cancerologie de la Loire
city: Saint-Nazaire
country: France
facility: Centre Etienne Dolet
city: Sainte Clotilde
country: France
facility: Clinique Sainte Clotilde
city: Strasbourg
country: France
facility: Clinique de l'Orangerie
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Toulon - Cedex
country: France
facility: Centre Hospitalier Intercommunal Toulon - La Seyne Sur Mer
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Tours
country: France
facility: Centre Hospitalier Universitaire Bretonneau de Tours
Study officials:
affiliation: Hopital Jean Minjoz
name: Xavier Pivot, MD, PhD
role: STUDY_CHAIR
References:
citation: Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espie M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporte I, Faure-Mercier C, Paget-Bailly S, Henriques J, Grouin JM; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet. 2019 Jun 29;393(10191):2591-2598. doi: 10.1016/S0140-6736(19)30653-1. Epub 2019 Jun 6.
citation: Jacquinot Q, Paget-Bailly S, Fumoleau P, Romieu G, Pierga JY, Espie M, Lortholary A, Nabholtz JM, Mercier CF, Pauporte I, Henriques J, Pivot X. Fluctuation of the left ventricular ejection fraction in patients with HER2-positive early breast cancer treated by 12 months of adjuvant trastuzumab. Breast. 2018 Oct;41:1-7. doi: 10.1016/j.breast.2018.06.001. Epub 2018 Jun 15.
citation: Curtit E, Pivot X, Henriques J, Paget-Bailly S, Fumoleau P, Rios M, Bonnefoi H, Bachelot T, Soulie P, Jouannaud C, Bourgeois H, Petit T, Tennevet I, Assouline D, Mathieu MC, Jacquin JP, Lavau-Denes S, Darut-Jouve A, Ferrero JM, Tarpin C, Levy C, Delecroix V, Trillet-Lenoir V, Cojocarasu O, Meunier J, Pierga JY, Kerbrat P, Faure-Mercier C, Blanche H, Sahbatou M, Boland A, Bacq D, Besse C, Thomas G, Deleuze JF, Pauporte I, Romieu G, Cox DG. Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes. Breast Cancer Res. 2017 Aug 22;19(1):98. doi: 10.1186/s13058-017-0888-4.
citation: Pivot X, Fumoleau P, Pierga JY, Delaloge S, Bonnefoi H, Bachelot T, Jouannaud C, Bourgeois H, Rios M, Soulie P, Jacquin JP, Lavau-Denes S, Kerbrat P, Cox D, Faure-Mercier C, Pauporte I, Gligorov J, Curtit E, Henriques J, Paget-Bailly S, Romieu G. Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort. Eur J Cancer. 2017 Aug;81:151-160. doi: 10.1016/j.ejca.2017.05.020. Epub 2017 Jun 16.
citation: Pivot X, Suter T, Nabholtz JM, Pierga JY, Espie M, Lortholary A, Khayat D, Pauporte I, Romieu G, Kramar A, Fumoleau P. Cardiac toxicity events in the PHARE trial, an adjuvant trastuzumab randomised phase III study. Eur J Cancer. 2015 Sep;51(13):1660-6. doi: 10.1016/j.ejca.2015.05.028. Epub 2015 Jul 7.
citation: Kramar A, Bachelot T, Madrange N, Pierga JY, Kerbrat P, Espie M, Fumoleau P, Pauporte I, Khayat D, Romieu G, Pivot X. Trastuzumab duration effects within patient prognostic subgroups in the PHARE trial. Ann Oncol. 2014 Aug;25(8):1563-70. doi: 10.1093/annonc/mdu177. Epub 2014 May 14.
citation: Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espie M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Tubiana-Mathieu N, Cany L, Catala S, Khayat D, Pauporte I, Kramar A; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013 Jul;14(8):741-8. doi: 10.1016/S1470-2045(13)70225-0. Epub 2013 Jun 11.