A Study of Trastuzumab Emtansine (Kadcyla) Plus Pertuzumab (Perjeta) Following Anthracyclines in Comparison With Trastuzumab (Herceptin) Plus Pertuzumab and a Taxane Following Anthracyclines as Adjuvant Therapy in Participants With Operable HER2-Positive Primary Breast Cancer

Breast Cancer Clinical Trial

Official title:

A Randomized, Multicenter, Open-Label, Phase III Trial Comparing Trastuzumab Plus Pertuzumab Plus a Taxane Following Anthracyclines Versus Trastuzumab Emtansine Plus Pertuzumab Following Anthracyclines as Adjuvant Therapy in Patients With Operable HER2-Positive Primary Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01966471
• Other study ID #: BO28407
• Secondary ID: 2012-004902-82
• Status: Completed
• Phase: Phase 3
• Start date: January 31, 2014
• Est. completion date: June 4, 2021

Study information

• Verified date: June 2022
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This two-arm, randomized, open-label, multicenter study will evaluate the efficacy and safety of trastuzumab emtansine in combination with pertuzumab versus trastuzumab in combination with pertuzumab and a taxane as adjuvant therapy in participants with human epidermal growth (HER) factor 2 (HER2)-positive primary invasive breast cancer. Following surgery and anthracycline-based chemotherapy, participants will receive either trastuzumab emtansine at a dose of 3.6 milligrams per kilogram (mg/kg) and pertuzumab at a dose of 420 milligrams (mg) intravenously (IV) every 3 weeks (q3w) or trastuzumab at a dose of 6 mg/kg and pertuzumab at a dose of 420 mg IV q3w in combination with a taxane.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1846
• Est. completion date: June 4, 2021
• Est. primary completion date: November 27, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (</=) 1
• Non-metastatic histologically confirmed primary invasive breast carcinoma that was operable
• HER2-positive breast cancer
• Known hormone receptor status of the primary tumor
• Adequately excised: participants must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy
• Pathological tumor-node-metastasis staging (Union for International Cancer Control-American Joint Committee on Cancer [UICC/AJCC] 7th edition): eligible participants must have either: Node-positive disease (pN more than or equal to [>/=] 1), any tumor size except T0, and any hormonal receptor status; or Node-negative disease (pN0) with pathologic tumor size >2.0 centimeters by standard local assessment and negative for estrogen receptor (ER) and progesterone receptor (PR) determined by a central pathology laboratory
• Participants with synchronous bilateral invasive disease are eligible only if both lesions are HER2-positive
• No more than 9 weeks (63 days) may elapse between definitive breast surgery (or the last surgery if additional resection required for breast cancer) and randomization
• Baseline left ventricular ejection fraction (LVEF) >/=55% measured by echocardiogram (ECHO; preferred) or multiple-gated acquisition (MUGA) scans
• Documentation on hepatitis B virus (HBV) and hepatitis C virus (HCV) serology is required
• Female participants of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception. For male participants with partners of childbearing potential, one highly effective form of contraception or two effective forms of contraception must be used. Contraception must continue for the duration of study treatment and for 6 months after the last dose of study treatment

Exclusion Criteria:

• History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma
• History of non-breast malignancies within the 5 years prior to randomization, except for carcinoma in situ (CIS) of the cervix, CIS of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin
• Any clinical T4 tumor as defined by tumor-node-metastasis classification in UICC/AJCC 7th edition, including inflammatory breast cancer
• For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment (for example, neoadjuvant or adjuvant), including but not limited to, chemotherapy, anti-HER2 therapy (for example, trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, neratinib, or other tyrosine kinase inhibitors), hormonal therapy, OR anti-cancer radiation therapy (RT) (intra-operative radiotherapy as a boost at the time of primary surgery is acceptable)
• Previous therapy with anthracyclines, taxanes, or HER2-targeted therapy for any malignancy
• History of DCIS and/or lobular CIS (LCIS) that was treated with any form of systemic chemotherapy, hormonal therapy, or RT to the ipsilateral breast where invasive cancer subsequently developed. Participants who had their DCIS/LCIS treated with surgery only and/or contralateral DCIS treated with radiation are allowed to enter the study
• Participants with contraindication to RT while adjuvant RT is clinically indicated
• Concurrent anti-cancer treatment in another investigational trial
• Cardiopulmonary dysfunction as defined by protocol: angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease, significant symptoms (Grade >/=2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia, myocardial infarction within 12 months prior to randomization, uncontrolled hypertension, evidence of transmural infarction on electrocardiogram (ECG), requirement for oxygen therapy
• Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes, or known infection with HIV
• Any known active liver disease. For participants who are known carriers of HBV/HCV, active hepatitis B/C infection must be ruled out per local guidelines
• Inadequate hematologic, renal or liver function
• Pregnant or lactating women
• Hypersensitivity to any of the study medications or any of the ingredients or excipients of these medications, including hypersensitivity to benzyl alcohol
• Chronic immunosuppressive therapies, including systemic corticosteroids

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Trastuzumab Emtansine
Trastuzumab emtansine IV infusion (duration 90 minutes) will be administered at 3.6 mg/kg q3w for up to 18 cycles (1 cycle = 21 days).
• Trastuzumab
Trastuzumab IV infusion (duration 90 minutes) will be administered at 8 mg/kg loading dose followed by 6 mg/kg IV q3w for up to 18 cycles (1 cycle = 21 days).
• Pertuzumab
Pertuzumab infusion (duration 60 minutes) will be administered at 840 mg loading dose followed by 420 mg IV q3w for up to 18 cycles (1 cycle = 21 days).
• Paclitaxel
IV infusion of paclitaxel 80 mg/m^2 once weekly may be administered concurrently with trastuzumab in combination with pertuzumab for 12 weeks.
• Epirubicin
3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using epirubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.
• Doxorubicin
3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using doxorubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.
• Docetaxel
IV infusion either docetaxel every 3 weeks (q3w) (at 100 milligram per square meter [mg/m^2] for 3 cycles (1 cycle = 21 days); at 75 mg/m2 for 4 cycles; or start at 75 mg/m^2 in the first cycle and escalate to 100 mg/m^2 if no dose limiting toxicity occurs, for a total of 3 cycles at minimum) may be administered concurrently with trastuzumab in combination with pertuzumab.
• Cyclophosphamide
3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using cyclophosphamide (FEC) may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.
• 5-Fluorouracil
3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using 5-fluorouracil, may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.

Locations

Country	Name	City	State
Australia	Burnside War Memorial Hospital, Clinical Trials Centre	Adelaide	South Australia
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	Frankston Hospital; Oncology/Haematology	Frankston	Victoria
Australia	Austin Hospital; Medical Oncology	Heidelberg	Victoria
Australia	St John of God Murdoch Hospital; Oncology West	Murdoch	Western Australia
Australia	Epworth HealthCare; Clinical Trials Centre	Richmond	Victoria
Australia	Haematology & Oncology Clinics of Australia Research Centre	South Brisbane	Queensland
Australia	Calvary Mater Newcastle; Medical Oncology	Waratah	New South Wales
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	Sint Augustinus Wilrijk, Apotheek	Wilrijk
Bosnia and Herzegovina	University Clinical Center of the Republic of Srpska	Banja Luka
Bosnia and Herzegovina	Clinic of Oncology, University Clinical Center Sarajevo	Sarajevo
Brazil	Hospital de Cancer de Barretos	Barretos	SP
Brazil	Hospital Araujo Jorge; Departamento de Ginecologia E Mama	Goiania	GO
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Brazil	Hospital Sao Lucas - PUCRS	Porto Alegre	RS
Brazil	Hospital Paulistano	Sao Paulo	SP
Brazil	Hospital Perola Byington	Sao Paulo	SP
Brazil	Hospital Sirio Libanes; Centro de Oncologia	Sao Paulo	SP
Brazil	Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP
Canada	Tom Baker Cancer Centre-Calgary	Calgary	Alberta
Canada	Queen Elizabeth II Health Sciences Centre; Oncology	Halifax	Nova Scotia
Canada	BC Cancer - Kelowna (Sindi Ahluwalia Hawkins Centre)	Kelowna	British Columbia
Canada	Kingston General Hospital	Kingston	Ontario
Canada	Cite de La Sante de Laval; Hemato-Oncologie	Laval	Quebec
Canada	London Regional Cancer Centre	London	Ontario
Canada	Credit Valley Hospital/Carlo Fidani Peel Regional Cancer Centre	Mississauga	Ontario
Canada	Regional health authority A vitalite health network	Moncton	New Brunswick
Canada	McGill University; Glen Site; Oncology	Montreal	Quebec
Canada	Southlake Regional Health Center; Community Care Clinic / Oncology	Newmarket	Ontario
Canada	Lions Gate Hospital	North Vancouver	British Columbia
Canada	Lakeridge Health Oshawa; Oncology	Oshawa	Ontario
Canada	Hopital du Saint Sacrement	Quebec City	Quebec
Canada	Sault Area Hospital	Sault Ste. Marie	Ontario
Canada	North York General Hospital	Toronto	Ontario
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Canada	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia
Canada	Windsor Regional Cancer Centre	Windsor	Ontario
Chile	Instituto Oncologico del sur	Temuco
Chile	ONCOCENTRO APYS; Oncología	Vina Del Mar
Colombia	Oncomedica S.A.	Monteria
Czechia	Masarykuv onkologicky ustav	Brno
Czechia	Fakultni Nemocnice Hradec Kralove; Dept of Radiotherapy & Oncology	Hradec Kralove
Czechia	MULTISCAN, s.r.o., Radiologicke centrum Pardubice	Pardubice
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
El Salvador	Hospital Diagnostico Escalón	San Salvador
France	Ico - Paul Papin	Angers
France	Clinique Sainte Catherine	Avignon
France	HOPITAL JEAN MINJOZ; Oncologie	Besancon
France	Institut Bergonie; Oncologie	Bordeaux
France	CHU de Brest - Hôpital de Morvan	Brest
France	Centre Francois Baclesse; Oncologie	Caen
France	Centre Jean Perrin; Oncologie	Clermont Ferrand
France	Centre Georges Francois Leclerc; Oncologie 3	Dijon
France	Clinique Victor Hugo; Chimiotherapie	Le Mans
France	Centre Oscar Lambret; Cancerologie Gynecologique	Lille
France	Centre Leon Berard; Departement Oncologie Medicale	Lyon
France	Centre D'Oncologie de Gentilly; Oncology	Nancy
France	Centre Antoine Lacassagne	Nice
France	Institut de cancerologie du Gard	Nimes
France	HOPITAL TENON; Cancerologie Medicale	Paris
France	Centre Armoricain de Radiotherapie, de Imagerie Medicale et de Oncologie (CARIO)	Plerin
France	Polyclinique De Courlancy; Centre Radiotherapie Oncologie	Reims
France	Centre Eugene Marquis; Service d'oncologie	Rennes
France	Ico Rene Gauducheau; Oncologie	Saint Herblain
France	Institut De Cancerologie De La Loire; Consult Oncologie Niveau 0	St Priest En Jarez
France	Centre Paul Strauss; Oncologie Medicale	Strasbourg
France	Institut d'oncologie de l'Orangerie; Chimiotherapie	Strasbourg
France	Institut Claudius Regaud; Departement Oncologie Medicale	Toulouse
France	Centre Alexis Vautrin; Oncologie Medicale	Vandoeuvre-les-nancy
Georgia	Chemotherapy and Immunotherapy Clinic Medulla	Tbilisi
Georgia	Khechinashvili University Hospital ;Breast Unit	Tbilisi
Georgia	LTD Institute of Clinical Oncology	Tbilisi
Germany	Klinikum Augsburg	Augsburg
Germany	Hochwaldkrankenhaus	Bad Nauheim
Germany	Frauenarzt-Zentrum Zehlendorf an der Teltower Eiche	Berlin
Germany	Gemeinschaftspraxis Dr. Bueckner und Dr. Nueckel	Bochum
Germany	BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie	Dresden
Germany	AGAPLESION Markus-Krankenhaus	Frankfurt
Germany	Städtische Kliniken Frankfurt am Main Höchst	Frankfurt
Germany	Praxis für Interdisziplinäre Onkologie und Hämatologie GbR	Freiburg
Germany	Dres.Jochen Wilke und Harald Wagner	Fürth
Germany	Niels-Stensen-Kliniken Franziskus-Hospital Harderberg GmbH	Georgsmarienhütte
Germany	Universitätsklinikum Hamburg-Eppendorf; Frauenklinik	Hamburg
Germany	Gynaekologisch-Onkologische Schwerpunktpraxis Prof. Dr. med. Lueck, Dr. Schrader und Dr. Noeding	Hannover
Germany	Medizinische Hochschule Hannover, Klinik für Frauenheilkunde und Geburtshilfe	Hannover
Germany	Praxis Dr.med. Katja Ziegler-Löhr	Köln
Germany	Klinikum Kulmbach; Frauenklinik	Kulmbach
Germany	Universitätsklinikum Schleswig-Holstein / Campus Lübeck; Klinik für Frauenheilkunde und Geburtshilfe	Lübeck
Germany	Klinikum Meiningen Klinik f.Gynäkologie und Geburtshilfe	Meiningen
Germany	Klinikum der Universität München; Campus Großhadern; Klinik und Poliklinik für Frauenheilkunde	Muenchen
Germany	Hämatologisch/Onkologische Praxis Prof. Dr. Decker, Studienzentrum	Ravensburg
Germany	Agaplesion Diakonieklinikum Rotenburg	Rotenburg/Wümme
Germany	Gynäkologie Kompetenzzentrum; Praxis Dr. med. Carsten Hielscher	Stralsund
Germany	Dres. Helmut Forstbauer, Carsten Ziske und Kollegen; Onkologische Schwerpunktpraxis	Troisdorf
Germany	GRN-Klinik Weinheim; Abt.Gynäkologie und Geburtshilfe	Weinheim
Germany	Klinikum Worms; Frauenklinik; Klinik für Gynäkologie und Geburtshilfe	Worms
Guatemala	Centro Oncológico Sixtino / Centro Oncológico SA	Guatemala
Guatemala	Grupo Angeles	Guatemala City
Hong Kong	Princess Margaret Hospital; Oncology	Hong Kong
Hong Kong	Tuen Mun Hospital; Clinical Oncology	Hong Kong
Hong Kong	Queen Mary Hospital; Dept of Surgery	Pokfulam
Hungary	Municipal Hospital of Uzsoki Utca; Centre of Oncoradiology	Budapest
Hungary	Orszagos Onkologiai Intezet; B Belgyogyaszati Osztaly	Budapest
Hungary	Debreceni Egyetem, Klinikai Kozpont, Onkologiai Klinika	Debrecen
Hungary	Szegedi Tudomanyegyetem, AOK, Szent-Gyorgyi Albert Klinikai Kozpont, Onkoterapias Klinika	Szeged
Israel	Chaim Sheba Medical Center; Oncology Dept	Ramat Gan
Israel	Sourasky / Ichilov Hospital; Oncology Department	Tel Aviv
Italy	Irccs Centro Di Riferimento Oncologico (CRO); Dipartimento Di Oncologia Medica	Aviano	Friuli-Venezia Giulia
Italy	Azienda Ospedaliero-Universitaria S.Orsola-Malpighi; Unità Operativa Oncologia Medica	Bologna	Emilia-Romagna
Italy	Ospedale Antonio Perrino; Oncologia Medica	Brindisi	Puglia
Italy	ASST DI CREMONA; Unità di Patologia Mammaria Senologia e Breast Unit	Cremona	Lombardia
Italy	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1	Milano	Lombardia
Italy	Ospedale San Raffaele	Milano	Lombardia
Italy	Humanitas Centro Catanese Di Oncologia; Oncologia Medica	Misterbianco (CT)	Sicilia
Italy	ASST DI MONZA; Oncologia Medica	Monza	Lombardia
Italy	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli	Campania
Italy	IOV - Istituto Oncologico Veneto - IRCCS; Oncologia Medica II	Padova	Veneto
Italy	Ospedale Misericordia E Dolce; Oncologia Medica	Prato	Toscana
Italy	Istituto Nazionale Tumori Regina Elena IRCCS	Roma	Lazio
Italy	Policlinico Universitario Campus Biomedico; Uoc Oncologia Medica	Roma	Lazio
Italy	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia
Italy	Azienda Ospedaliera S. Maria - Terni; Oncologia	Terni	Umbria
Japan	Aichi Cancer Center Hospital, Breast Oncology	Aichi
Japan	Nagoya City University Hospital; Breast Surgery	Aichi
Japan	Natl Hosp Org Shikoku; Cancer Ctr, Surgery	Ehime
Japan	National Hospital Organization Kyushu Cancer Center;Breast Oncology	Fukuoka
Japan	Gunma Prefectural Cancer Center; Breast Oncology	Gunma
Japan	Gunma University Hospital; Department of Breast and Endocrine Surgery	Gunma
Japan	Hiroshima City Hiroshima Citizens Hospital; Breast Surgery	Hiroshima
Japan	Hiroshima University Hospital; Breast Surgery	Hiroshima
Japan	Hyogo College Of Medicine; Breast And Endocrine Surgery	Hyogo
Japan	Iwate Med Univ School of Med; Surgery	Iwate
Japan	Sagara Hospital; Breast Surgery	Kagoshima
Japan	St. Marianna University School of Medicine Hospital, Breast and Endocrine Surgery	Kanagawa
Japan	Tokai University Hospital, Breast Surgery	Kanagawa
Japan	Kumamoto City Hospital, Breast and Endocrine Surgery	Kumamoto
Japan	Kumamoto Shinto General Hospital; Breast Cancer Center	Kumamoto
Japan	Kyoto University Hospital; Breast Surgery	Kyoto
Japan	Niigata Cancer Ctr Hospital; Breast Surgery	Niigata
Japan	Kawasaki Medical School Hospital; Breast and Thyroid Surgery	Okayama
Japan	Naha-nishi Clinic; Surgery	Okinawa
Japan	National Hospital Organization Osaka National Hospital; Breast Surgery	Osaka
Japan	Osaka International Cancer Institute; Breast and Endocrine Surgery	Osaka
Japan	Saitama Cancer Center, Breast Oncology	Saitama
Japan	Saitama Medical University International Medical Center; Breast Oncology	Saitama
Japan	Shizuoka Cancer Center; Breast Surgery	Shizuoka
Japan	Shizuoka General Hospital; Breast Surgery	Shizuoka
Japan	Jichi Medical University; Breast Oncology	Tochigi
Japan	National Cancer Center Hospital; Medical Oncology	Tokyo
Japan	Showa University Hospital; Breast Surgery	Tokyo
Japan	St. Luke's Internat. Hospital, Breast Surgical Oncology	Tokyo
Japan	The Cancer Inst. Hosp. of JFCR; Breast Oncology Center	Tokyo
Japan	Tokyo Medical Uni. Hospital; Breast Oncology	Tokyo
Japan	Tokyo Metropolitan; Komagome Hospital, Surgery	Tokyo
Korea, Republic of	Ajou Uni Hospital; Medical Oncology	Gyeonggi-do
Korea, Republic of	National Cancer Center; Medical Oncology	Gyeonggi-do
Korea, Republic of	Samsung Medical Centre; Division of Hematology/Oncology	Seoul
Korea, Republic of	Seoul National Uni Hospital; Dept. of Internal Medicine/Hematology/Oncology	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Mexico	Instituto Nacional De Cancerologia; Oncology; Tumores Mamarios	Distrito Federal
Mexico	Fundacion Rodolfo Padilla Padilla A.C.	León
Mexico	Consultorio de Medicina Especializada; Dentro de Condominio San Francisco	Mexico City
Mexico	Hospital San Jose Del Tec. de Monterrey; Oncology	Monterrey
Norway	Oslo universitetssykehus HF, Ullevål, Kreftsenteret	Oslo
Norway	Helse Stavanger HF, Stavanger Universitetssjukehus; Klinikk for Blod og kreftsykdommer	Stavanger
Panama	Centro Hemato Oncologico Panama	Panama
Peru	Clinica de Especialidades Medicas	Lima
Peru	Clinica Internacional, Sede San Borja; Unidad de Investigacion de Clínica Internacional	Lima
Peru	Clinica San Borja	Lima
Peru	Instituto Oncologico Miraflore	Miraflores
Philippines	San Juan de Dios Hospital;Oncology Unit	Pasay
Philippines	East Avenue Medical Center	Quezon City
Poland	Bialostockie Centrum Onkologii; Oddzial Onkologii Klinicznej	Bialystok
Poland	Centrum Onkologii;Im. Franciszka Lukaszczyka;Onkologii	Bydgoszcz
Poland	Uniwersyteckie Centrum Kliniczne, Klinika Onkologii i Radioterapii	Gdansk
Poland	Szpital Uniwersytecki w Krakowie, Oddzial Kliniczny Kliniki Onkologii	Kraków
Poland	Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii; Poradnia Chemioterapii	Lodz
Poland	Centrum Onkologii Ziemi LUBELSKIEJ im. Sw Jana z Dukli, I oddz. Chemioterapii	Lublin
Poland	Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina, Klinika Onkologii	Otwock
Poland	Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr	Warszawa
Romania	Institutul Oncologic Prof. Dr. Al. Trestioreanu Bucuresti	Bucuresti
Romania	Prof. Dr. I. Chiricuta Institute of Oncology	Cluj Napoca
Romania	Cluj Clinical County Hospital; Oncology Dept	Cluj-Napoca
Romania	Regional Institute of Oncology Iasi	Iasi
Russian Federation	Ivanovo Regional Oncology Dispensary	Ivanovo
Russian Federation	Republican Clinical Oncologic Dispensary of Republic Of Tatarstan	Kazan
Russian Federation	FSBI Russian Oncology Research Center n.a. Blokhin of MOH RF	Moscow
Russian Federation	State Inst. Of Healthcare Orenburg Regional Clinical Oncology Dis	Orenburg
Russian Federation	SBI for HPE "Ryazan State Medical University n.a. I.P. Pavlov" of MoH of RF	Ryazan
Russian Federation	Scientific Research Institute n.a. N.N. Petrov	Saint Petersburg
Russian Federation	SBI of Healthcare Samara Regional Clinical Oncology Dispensary	Samara
Singapore	National Cancer Centre; Medical Oncology	Singapore
Singapore	National University Hospital; National University Cancer Institute, Singapore (NCIS)	Singapore
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital Duran i Reynals; Oncologia	Barcelona
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Hospital de Cruces; Servicio de Oncologia	Bilbao	Vizcaya
Spain	Hospital Universitario de Canarias;servicio de Oncologia	La Laguna	Tenerife
Spain	Centro Oncologico MD Anderson Internacional; Servicio de Oncologia	Madrid
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid
Spain	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga
Spain	Hospital Universitario Virgen de Arrixaca; Servicio de Oncologia	Murcia
Spain	Hospital Clínico Universitario de Valencia; Servicio de Oncología	Valencia
Spain	Hospital Universitario Miguel Servet; Servicio Oncologia	Zaragoza
Sweden	Sahlgrenska Universitetssjukhuset; Jubileumskliniken	Göteborg
Sweden	Universitetssjukhuset Örebro, Onkologiska kliniken	Örebro
Sweden	Akademiska sjukhuset, Onkologkliniken	Uppsala
Switzerland	Kantonsspital Graubünden Medizin Onkologie; Onkologie und Hämatologie	Chur
Switzerland	Luzerner Kantonsspital; Medizinische Onkologie	Luzern
Switzerland	Brust-Zentrum Zürich AG Seefeldstrasse 214 Zürich	Zürich
Taiwan	Changhua Christian Hospital; Dept of Surgery	Changhua
Taiwan	Kaohsiung Medical Uni Chung-Ho Hospital; Dept of Surgery	Kaohsiung
Taiwan	Taichung Veterans General Hospital; Dept of Surgery	Taichung
Taiwan	National Taiwan Uni Hospital; General Surgery	Taipei
Taiwan	Tri-Service General Hospital, Division of General Surgery	Taipei
Taiwan	VETERANS GENERAL HOSPITAL; Department of General Surgery	Taipei
Thailand	Chulalongkorn Hospital; Medical Oncology	Bangkok
Thailand	Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology	Bangkok
Thailand	Chiang Rai Prachanukroh Hospital; Department Of Medicine	Chiang Rai
Thailand	Buddhachinaraj Phitsanulok Hospital; Chemotherapy Unit ; Department of Medicine	Phitsanuok
Ukraine	State Medical Academy; Oncology	Dnipropetrovsk
Ukraine	Lviv State Oncological Regional Treatment and Diagnostic Center	Lviv
United Kingdom	Velindre Cancer Centre; Oncology Dept	Cardiff
United Kingdom	Cheltenham General Hospital; Gloucestershire Oncology Centre	Cheltenham
United Kingdom	Royal Cornwall Hospital; Dept of Clinical Oncology	Cornwall
United Kingdom	University Hospital Coventry; InHANSE Unit and Clinical Trials Cancer Treatment Centre	Coventry
United Kingdom	Western General Hospital; Edinburgh Breast Unit	Edinburgh
United Kingdom	Royal Devon & Exeter Hospital; Oncology Centre	Exeter
United Kingdom	Royal Surrey County Hospital; St. Lukes Cancer Centre	Guildford
United Kingdom	Leicester Royal Infirmary; Dept. of Medical Oncology	Leicester
United Kingdom	Charing Cross Hospital	London
United Kingdom	Royal Marsden Hospital - Fulham; Oncology Department	London
United Kingdom	Maidstone Hospital; Kent Oncology Centre	Maidstone
United Kingdom	Christie Hospital; Breast Cancer Research Office	Manchester
United Kingdom	Freeman Hospital; Northern Centre For Cancer Care	New Castle Upon Tyne
United Kingdom	Mount Vernon Cancer Centre	Northwood
United Kingdom	Nottingham City Hospital; Oncology	Nottingham
United Kingdom	Peterborough City Hospital, Edith Cavell Campus; Oncology Department	Peterborough
United Kingdom	Queen Alexandra Hospital; Portsmouth Haematology & Oncology Centre, Level B	Portsmouth
United Kingdom	Weston Park Hospital; Cancer Clinical Trials Centre	Sheffield
United Kingdom	Musgrove Park Hospital; Department Clinical Research, Beacon Centre	Somerset
United Kingdom	Uni Hospital of North Staffordshire; Staffordshire Oncology Centre	Stoke-on-Trent
United Kingdom	Royal Marsden Hospital; Dept of Medical Oncology	Sutton
United Kingdom	Yeovil District Hospital; Macmillan Cancer Unit	Yeovil
United States	Anne Arundel Health System Research Instit-Annapolis Oncology Ctr	Annapolis	Maryland
United States	University Cancer & Blood Center, LLC; Research	Athens	Georgia
United States	Georgia Cancer Specialists	Atlanta	Georgia
United States	Mercy Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Med Ctr	Boston	Massachusetts
United States	Dana Farber Cancer Inst.	Boston	Massachusetts
United States	Wellmont Medical Associates	Bristol	Virginia
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia Health System; Hematology/Oncology Division	Charlottesville	Virginia
United States	SCRI Tennessee Oncology Chattanooga	Chattanooga	Tennessee
United States	Oncology Hematology Care Inc	Cincinnati	Ohio
United States	Memorial Sloan-Kettering Cancer Center	Commack	New York
United States	Henry Ford Hospital; Hematology Oncology	Detroit	Michigan
United States	Karmanos Cancer Institute..	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Holy Cross Hospital	Fort Lauderdale	Florida
United States	Florida Cancer Specialists; SCRI	Fort Myers	Florida
United States	The Center for Cancer and Blood Disorders - Fort Worth	Fort Worth	Texas
United States	West Clinic	Germantown	Tennessee
United States	Cone Health Cancer Center	Greensboro	North Carolina
United States	Indiana University	Indianapolis	Indiana
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	ProHEALTH Care Associates LLP	Lake Success	New York
United States	Dartmouth Hitchcock Med Center	Lebanon	New Hampshire
United States	Central Georgia Cancer Care PC	Macon	Georgia
United States	Sarah Cannon Cancer Center - Tennessee Oncology, Pllc	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Kaiser Permanente - Oakland	Oakland	California
United States	Mercy Clinic Oklahoma Communties, Inc	Oklahoma City	Oklahoma
United States	Magee-Woman's Hospital	Pittsburgh	Pennsylvania
United States	Quincy Medical Group; Canc Ctr at Blessing Hosp	Quincy	Illinois
United States	Virginia Commonwealth University - Massey Cancer Center	Richmond	Virginia
United States	Kaiser Permanente - Roseville; Oncology Pharmacy	Roseville	California
United States	Kaiser Permanente - Sacramento; Oncology Pharmacy	Sacramento	California
United States	UC Davis Cancer Center; Oncology	Sacramento	California
United States	US oncology research at Minnesota Oncology	Saint Paul	Minnesota
United States	Florida Cancer Specialists; Saint Petersburg	Saint Petersburg	Florida
United States	Blue Ridge Cancer Care - Salem	Salem	Virginia
United States	Southern California Kaiser Permanente	San Diego	California
United States	Kaiser Permanente - San Jose	San Jose	California
United States	Kaiser Permanente - San Leandro	San Leandro	California
United States	HonorHealth Research Institute - Bisgrove	Scottsdale	Arizona
United States	University of Washington	Seattle	Washington
United States	Kaiser Permanente - South SF; Oncology Clinical trials	South San Francisco	California
United States	Mercy Medical Research Institute	Springfield	Missouri
United States	Stanford University School of Medicine	Stanford	California
United States	Carle Cancer Center	Urbana	Illinois
United States	Kaiser Permanente - Vallejo	Vallejo	California
United States	Kaiser Permanente - Walnut Creek; Oncology Pharmacy	Walnut Creek	California
United States	Cancer Center of Kansas	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Bosnia and Herzegovina,  Brazil,  Canada,  Chile,  Colombia,  Czechia,  El Salvador,  France,  Georgia,  Germany,  Guatemala,  Hong Kong,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Norway,  Panama,  Peru,  Philippines,  Poland,  Romania,  Russian Federation,  Singapore,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Invasive Disease-Free Survival (IDFS) in the Node-Positive Subpopulation	IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer [bc] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site [other than the three sites mentioned above]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population was estimated using the Kaplan-Meier method and estimated the probability of a participant being event-free after 3 years after randomization.	Last participant randomized to data cut-off date of 27 November 2019 (approximately 70 months). The 3 year IDFS event-free rate was assessed based on the data collected for each participant considering the cut-off date mentioned above.
Primary	Invasive Disease-Free Survival (IDFS) in the Overall Population	IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer [bc] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site [other than the three sites mentioned above]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.	First participant randomized up to approximately 7.5 years
Secondary	IDFS Plus Second Primary Non-Breast Cancer	IDFS including second primary non-breast cancer was defined the same way as IDFS for the primary endpoint but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and carcinoma in situ (CIS) of any site).	Baseline up to approximately 70 months
Secondary	Disease-Free Survival (DFS)	DFS was defined as time between randomization and first occurrence of IDFS, second primary non-breast cancer and contralateral or ipsilateral ductal carcinoma in situ (DCIS).	Baseline up to approximately 70 months
Secondary	Distant Recurrence-Free Interval (DRFI)	DRFI was defined as time between randomization and first occurrence of distant breast cancer recurrence.	Baseline up to approximately 70 months
Secondary	Overall Survival (OS)	OS was defined as the time from randomization to death due to any cause.	First participant randomized up to approximately 7.5 years
Secondary	Percentage of Participants With Adverse Events	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0).	From randomization to approximately 7.5 years
Secondary	Percentage of Participants With Decrease in Left Ventricular Ejection Fraction (LVEF) From Baseline Over Time	LVEF was assessed using either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans.	First participant randomized up to approximately 7.5 years.
Secondary	European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score	The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 7 - 15 points considered to be a clinically meaningful detioration to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1).	Baseline, Cycles 1, 2, 3, 4, 5, 9, 14, End of Treatment, Follow-up Month 6, Follow-up Month 12, Follow-up Month 18
Secondary	EORTC Quality of Life Questionnaire-Breast Cancer 23 (QLQ-BR23) Score	EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30. There are four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated improvement in quality of life (QOL) while negative change from baseline indicated a deterioration. For symptom scales, positive change from baseline indicated deterioration and negative change indicated improvement.	Baseline, Cycles 1, 2, 3, 4, 5, 9, 14, End of Treatment, Follow-up Month 6, Follow-up Month 12, Follow-up Month 18
Secondary	Time to Clinically Meaningful Deterioration in the Global Health Status/ Quality of Life and Functional (Physical, Role, and Cognitive) Subscales of the QLQ-C30 From First HER2-Targeted Treatment	The time to clinically meaningful deterioration in the global health status/Quality of life and Functional (Physical, Role, and Cognitive) subscales of the the QLQ-C30 was assessed from the time of the HER2-Targeted treatment to the worsening in the respective scales. Clinically meaningful deterioration is defined as a decrease in score of 10 points in Physical functioning and HRQoL; decrease of 7 points in Cognitive functioning, and decrease of 14 points in Role functioning.	From start of HER-2 targeted treatment up to 18 months after treatment discontinuation. The median time to clinically meaningful deterioration was assessed based on the data collection described above.