A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Participants With Metastatic Breast Cancer (MARIANNE)

Breast Cancer Clinical Trial

Official title:

A Randomized, 3 Arm, Multicenter, Phase III Study to Evaluate the Efficacy and the Safety of T-DM1 Combined With Pertuzumab or T-DM1 Combined With Pertuzumab-Placebo (Blinded for Pertuzumab), Versus the Combination of Trastuzumab Plus Taxane, as First Line Treatment in HER2 Positive Progressive or Recurrent Locally Advanced or Metastatic Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01120184
• Other study ID #: BO22589
• Secondary ID: 2009-017905-13
• Status: Completed
• Phase: Phase 3
• Start date: July 31, 2010
• Est. completion date: September 16, 2016

Study information

• Verified date: February 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized, 3-arm, multicenter, phase III study will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) with pertuzumab or trastuzumab emtansine (T-DM1) with pertuzumab-placebo (blinded for pertuzumab), versus the combination of trastuzumab (Herceptin) plus taxane (docetaxel or paclitaxel) in participants with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer. Participants will be randomized to 1 of 3 treatment arms (Arms A, B or C). Arm A will be open-label, whereas Arms B and C will be blinded.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1095
• Est. completion date: September 16, 2016
• Est. primary completion date: September 30, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult participants >/=18 years of age
• HER2-positive breast cancer
• Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and be a candidate for chemotherapy. Participants with locally advanced disease must have recurrent or progressive disease, which must not be amenable to resection with curative intent.
• Participants must have measurable and/or non-measurable disease which must be evaluable per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
• Adequate organ function as determined by laboratory results

Exclusion Criteria:

• History of prior (or any) chemotherapy for metastatic breast cancer or recurrent locally advanced disease
• An interval of <6 months from the last dose of vinca-alkaloid or taxane cytotoxic chemotherapy until the time of metastatic diagnosis
• Hormone therapy <7 days prior to randomization
• Trastuzumab therapy and/or lapatinib (neo- or adjuvant setting) <21 days prior to randomization
• Prior trastuzumab emtansine or pertuzumab therapy

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• docetaxel
75 mg/m2 or 100 mg/m2 intravenously every 3 weeks for a minimum of 6 cycles.
• paclitaxel
80 mg/m2 intravenously weekly for a minimum of 18 weeks
• pertuzumab
840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles
• pertuzumab-placebo
840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles
• trastuzumab [Herceptin]
trastuzumab [Herceptin] doses when administered with docetaxel: 8 mg/kg intravenously on cycle 1 followed by 6 mg/kg every 3 weeks in subsequent cycles or trastuzumab (Herceptin) doses when administered with paclitaxel: 4 mg/kg intravenously on day 1 of cycle 1 followed by 2 mg/kg weekly starting on day 8 of cycle 1.
• trastuzumab emtansine
3.6 mg/kg intravenously every 3 weeks

Locations

Country	Name	City	State
Argentina	Fundación Investigar	Buenos Aires
Argentina	Centro Medico San Roque	San Miguel de Tucuman
Australia	Royal Adelaide Hospital; Oncology	Adelaide	South Australia
Australia	Wesley Medical Centre; Clinic For Haematology and Oncology	Auchenflower	Queensland
Australia	Peter Maccallum Cancer Institute; Medical Oncology	Melbourne	Victoria
Australia	Mater Misericordiae Hospital; Chemotherapy Cottage	Sydney	New South Wales
Australia	Calvary Mater Newcastle; Medical Oncology	Waratah	New South Wales
Austria	Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.	Salzburg
Austria	Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie	Wien
Bahamas	Oncology Consultants Limited	Nassau
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	Clinique Ste-Elisabeth	Namur
Belgium	Sint Augustinus Wilrijk	Wilrijk
Bosnia and Herzegovina	University Clinical Centre of the Republic of Srpska	Banja Luka
Bosnia and Herzegovina	Clinic of Oncology, University Clinical Center Sarajevo	Sarajevo
Brazil	Clinica de Neoplasias Litoral	Itajai	SC
Brazil	Liga Norte Riograndense Contra O Câncer	Natal	RN
Brazil	Clinica de Oncologia de Porto Alegre - CliniOnco	Porto Alegre	RS
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Brazil	Hospital Sao Lucas - PUCRS	Porto Alegre	RS
Brazil	*X*Instituto Nacional do Cancer - INCA	Rio de Janeiro	RJ
Brazil	Hospital Perola Byington	Sao Paulo	SP
Brazil	Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP
Canada	Cross Cancer Institute; Clinical Trials	Edmonton	Alberta
Canada	CHU de Québec ? Hôpital du Saint-Sacrement / ONCOLOGY	Quebec
Canada	Cuse - Centre Universitaire De Sante; Site Fleurimont	Sherbrooke	Quebec
Canada	North York General Hospital	Toronto	Ontario
Colombia	Clinica del Country	Bogota
Colombia	Instituto Colombiano Para El Avance De La Medicina: Icamedic	Bucaramanga
Colombia	Centro Medico Imbanaco	Cali
Colombia	Instituto Cancerologico de Nariño	Pasto
Czechia	Masarykuv onkologicky ustav	Brno
Czechia	Fakultni nemocnice Olomouc; Onkologicka klinika	Olomouc
Czechia	Fakultni Nemocnice Na Bulovce; Ustav Radiacni Onkologie	Praha
Czechia	Fakultni Poliklinika Vseobecne Fakultni Niemocnice; Onkologicka Klinika	Praha 2
Denmark	Vejle Sygehus; Onkologisk Afdeling	Vejle
France	HOPITAL JEAN MINJOZ; Oncologie	Besancon
France	Centre Jean Perrin; Hopital De Jour	Clermont Ferrand
France	Centre Oscar Lambret; Senologie	Lille
France	Institut Paoli Calmettes; Oncologie Medicale	Marseille
France	Institut régional du Cancer Montpellier	Montpellier
France	Centre D'Oncologie de Gentilly; Oncology	Nancy
France	Hopital Saint Louis; Service Onco Thoracique	Paris
France	HOPITAL TENON; Cancerologie Medicale	Paris
France	Institut Curie; Oncologie Medicale	Paris
France	Chu La Miletrie; Radiotherapie	Poitiers
France	Centre Rene Huguenin; ONCOLOGIE GENETIQUE	Saint Cloud
France	Institut de Cancerologie de La Loire; Radiotherapie	St Priest En Jarez
Germany	Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum	Essen
Germany	Universitätsklinikum Halle (Saale); Universitätsklinik Und Poliklinik Für Gynäkologie	Halle
Germany	Facharztzentrum Eppendorf, Studien GbR	Hamburg
Germany	MVZ Onko Medical GmbH Hannover, Ralf Lohse (Geschäftsführer)	Hannover
Germany	Nationales Centrum für Tumorerkrankungen (NCT) ; Gyn. Onk. Frauenklinik; Uniklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Magdeburg; Frauenheilkunde & Geburtshilfe	Magdeburg
Germany	Universitätsmedizin Mainz; Klinik u. Poliklinik f. Geburtshilfe u. Frauenheilkunde	Mainz
Germany	Mühlenkreiskliniken; Johannes Wesling Klinikum Minden; Klinik für Frauenheilkunde und Geburtshilfe	Minden
Germany	Rotkreuzklinikum München; Frauenklinik	Muenchen
Germany	Klinikum Mutterhaus der Borromaeerinnen gGmbH; Haematologie/Onkologie	Trier
Greece	Alexandras General Hospital of Athens; Oncology Department	Athens
Greece	Univ General Hosp Heraklion; Medical Oncology	Heraklion
Greece	University Hospital of Larissa; Oncology	Larissa
Guatemala	Centro Oncológico Sixtino / Centro Oncológico SA	Guatemala
Guatemala	Grupo Angeles	Guatemala City
Hungary	Semmelweis Egyetem Aok; Iii.Sz. Belgyogyaszati Klinika	Budapest
Hungary	Semmelweis Egyetem Onkologiai Központ	Budapest
Hungary	Szent Margit Hospital; Dept. of Oncology	Budapest
Hungary	Pécsi Tudományegyetem; Klinikai Központ Onkoterápiás Intézet	Pécs
Italy	Centro Catanese Di Oncologia; Oncologia Medica	Catania	Sicilia
Italy	Campus Universitario S.Venuta; Centro Oncologico T.Campanella	Catanzaro	Calabria
Italy	IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica	Meldola	Emilia-Romagna
Italy	Ospedale Papardo- Piemonte;Oncologia Medica	Messina	Sicilia
Italy	Istituto Europeo Di Oncologia	Milano	Lombardia
Italy	A.O. Universitaria Policlinico Di Modena; Ematologia	Modena	Emilia-Romagna
Italy	Fondazione Salvatore Maugeri	Pavia	Lombardia
Italy	Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica	Perugia	Umbria
Italy	Ospedale Misericordia E Dolce; Oncologia Medica	Prato	Toscana
Italy	Arcispedale Santa Maria Nuova; Oncologia	Reggio Emilia	Emilia-Romagna
Italy	Ospedale Degli Infermi; Divisione Di Oncologia	Rimini	Emilia-Romagna
Italy	IRCCS Istituto Clinico Humanitas; Oncologia	Rozzano (MI)	Lombardia
Italy	Azienda Ospedaliero-Universitaria Dipartimento Interaziendale Di Oncologia	Udine	Friuli-Venezia Giulia
Japan	Aichi Cancer Center Hospital, Breast Oncology	Aichi
Japan	Natl Hosp Org Shikoku; Cancer Ctr, Surgery	Ehime
Japan	National Hospital Organization Kyushu Cancer Center;Breast Oncology	Fukuoka
Japan	Gifu University Hospital; Digestive Surgery	Gifu
Japan	Hiroshima University Hospital; Breast Surgery	Hiroshima
Japan	National Hospital Organization Hokkaido Cancer Center; Breast Surgery	Hokkaido
Japan	Hyogo Cancer Center; Breast Surgery	Hyogo
Japan	Hyogo College Of Medicine; Breast And Endocrine Surgery	Hyogo
Japan	Kanazawa University Hospital; Breast Oncology	Ishikawa
Japan	Iwate Med Univ School of Med; Surgery	Iwate
Japan	Sagara Hospital; Breast Surgery	Kagoshima
Japan	Tokai University Hospital, Breast Surgery	Kanagawa
Japan	Kumamoto City Hospital, Breast and Endocrine Surgery	Kumamoto
Japan	Kumamoto University Hospital; Breast and Endocrine Surgery	Kumamoto
Japan	Kyoto University Hospital; Breast Surgery	Kyoto
Japan	Tohoku University Hospital; General Surgery	Miyagi
Japan	Niigata Cancer Ctr Hospital; Breast Surgery	Niigata
Japan	Kawasaki Medical School Hospital; Breast and Thyroid Surgery	Okayama
Japan	National Hospital Organization Osaka National Hospital; Breast Surgery	Osaka
Japan	Osaka University Hospital; Breast and Endocrine Surgery	Osaka
Japan	Saitama Cancer Center, Breast Oncology	Saitama
Japan	Saitama Medical University International Medical Center; Medical Oncology	Saitama
Japan	Shizuoka Cancer Center; Breast Surgery	Shizuoka
Japan	Shizuoka General Hospital; Breast Surgery	Shizuoka
Japan	National Cancer Center Hospital; Medical Oncology	Tokyo
Japan	The Cancer Inst. Hosp. of JFCR; Breast Oncology Center	Tokyo
Japan	Tokyo Medical Uni. Hospital; Breast Oncology	Tokyo
Japan	Toranomon Hospital; Breast and Endocrine Surgery	Tokyo
Korea, Republic of	Seoul National University Bundang Hospital; Hematology Medical Oncology	Gyeonggi-do
Korea, Republic of	Asan Medical Center, Uni Ulsan Collegemedicine; Dept.Internal Medicine / Divisionhematology/Oncology	Seoul
Korea, Republic of	Korea University Guro Hospital; Oncology	Seoul
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
Malaysia	Pantai Hospital Kuala Lumpur; Dept of Oncology & Radiotherapy	Kuala Lumpur	FED. Territory OF Kuala Lumpur
Malaysia	Beacon International Specialist Centre	Petaling Jaya, Selangor	Selangor
Malaysia	Sunway Medical Centre	Selangor
Mexico	Centro de Investigacion; Clinica Del Pacifico	Acapulco	Guerrero
Mexico	Centenario Hospital Miguel Hidalgo	Aguascalientes
Mexico	Centro Universitario Contra El Cancer	Monterrey	Nuevo LEON
Mexico	Oaxaca Site Management Organization	Oaxaca de Juárez	Oaxaca
Mexico	Hospital Privado San Jose; Oncologia	Obregon	Sonora
Mexico	Centro Oncológico Estatal; ISSSEMYM Oncología	Toluca
New Zealand	Auckland city hospital; Auckland Regional Cancer Centre and Blood Service	Auckland
New Zealand	Waikato Hospital; Regional Cancer Center	Hamilton
North Macedonia	Private Health Organization Acibadem Sistina Hospital	Skopje
Panama	The Panama Clinic	Panama
Peru	Hospital Nacional Carlos Alberto Seguin Escobedo-Essalud; Oncology & Haemathology	Arequipa
Peru	Hospital Nacional Edgardo Rebagliati Martins; Oncologia	Lima
Peru	Unidad de Investigacion Oncologia Clinica ? Piura; Unidad de Oncología Clínica	Piura
Philippines	Cebu Cancer Institute; Perpetual Succour Hospital	Cebu City
Philippines	Cardinal Santos Medical Center	San Juan
Poland	Centrum Onkologii;Im. Franciszka Lukaszczyka;Onkologii	Bydgoszcz
Poland	Medical University of Gdansk	Gdansk
Poland	Centrum Onkologii, Instytut, Klinika Chemioterapii; Oddzial Chemoterapii	Krakow
Poland	COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej	Lublin
Poland	Cent.Onkologii-Instytut im. M. S-Curie, Klinika Now. Piersi i Chirurgii Rekon	Warszawa
Portugal	IPO do Porto; Servico de Oncologia Medica	Porto
Romania	Coltea Hospital; Oncology	Bucharest
Romania	Prof. Dr. I. Chiricuta Institute of Oncology	Cluj Napoca
Romania	Cluj Clinical County Hospital; Oncology Dept	Cluj-Napoca
Russian Federation	Ivanovo Regional Oncology Dispensary	Ivanovo
Russian Federation	Clinical Oncology Dispensary of Ministry of Health of Tatarstan	Kazan	Tatarstan
Russian Federation	Moscow city oncology hospital; #62 of Moscow Healthcare Department	Moscow	Moskovskaja Oblast
Russian Federation	Blokhin Cancer Research Center; Combined Treatment	Moskva	Moskovskaja Oblast
Russian Federation	State Budget Institution of Healthcare of Stavropol region Pyatigorsk Oncology Dispensary	Pyatigorsk	Stavropol
Russian Federation	Ryazan State Medical University Named after I.P.Pavlov	Ryazan	Rjazan
Russian Federation	SBI of Healthcare Samara Regional Clinical Oncology Dispensary	Samara
Russian Federation	SBI of Healthcare of Stavropol region Stavropol Regional Clinical Oncology Dispensary	Stavropol
Russian Federation	Tula Regional Oncology Dispensary	Tula
Russian Federation	GUZ Vladimir Regional Clinical Oncological Dispensary	Vladimir
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital General Universitario de Elche; Servicio de Oncologia	Elche	Alicante
Spain	Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia	Jaen
Spain	Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología	La Coruña
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	Hospital Universitario La Paz; Servicio de Oncologia	Madrid
Spain	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Sant Andreu de La Barca	Barcelona
Spain	Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia	Santiago de Compostela	LA Coruña
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
Sweden	Skånes Universitetssjukhus; Kliniska Forskningsenheten Onkologimottagning medicinsk behandling	Malmö
Switzerland	Kantonsspital Baden; Medizinische Klinik, Onkologie	Baden
Switzerland	Universitaetsspital Basel; Onkologie	Basel
Switzerland	Kantonsspital Graubünden Medizin Onkologie; Onkologie und Hämatologie	Chur
Taiwan	Changhua Christian Hospital; Hematology-Oncology	Changhua
Taiwan	Kaohsiung Medical Uni Chung-Ho Hospital; Dept of Surgery	Kaohsiung
Taiwan	National Taiwan Uni Hospital; Dept of Oncology	Taipei
Taiwan	Tri-Service General Hospital; Hematology and Oncology	Taipei
Thailand	Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology	Bangkok
Thailand	National Cancer Inst.	Bangkok
Thailand	Rajavithi Hospital; Division of Medical Oncology	Bangkok
Thailand	Ramathibodi Hospital; Dept of Med.-Div. of Med. Onc	Bangkok
Thailand	Maharaj Nakorn Hospital; Internal Medicine	Chiang Mai
Thailand	Songklanagarind Hospital; Department of Oncology	Songkhla
Turkey	Baskent University Adana Dr. Turgut Noyan Practice and Research Hospital; Medical Oncology	Adana
Turkey	Cukurova Uni Faculty of Medicine; Medical Oncology	Adana
Turkey	Gazi Uni Medical Faculty Hospital; Oncology Dept	Ankara
Turkey	Ege Uni Medical Faculty Hospital; Oncology Dept	Izmir
United Kingdom	Bristol Haematology and Oncology centre	Bristol
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	Royal Cornwall Hospital; Dept of Clinical Oncology	Cornwall
United Kingdom	The Beatson West of Scotland Cancer Centre; Cancer Clinical Trials Unit	Glasgow
United Kingdom	Leicester Royal Infirmary; Dept. of Medical Oncology	Leicester
United Kingdom	Guys Hospital; Management Offices	London
United Kingdom	Royal Free Hospital; Dept of Oncology	London
United Kingdom	Royal Marsden Hospital; Dept of Med-Onc	London
United Kingdom	Christie Hospital; Breast Cancer Research Office	Manchester
United Kingdom	Nottingham City Hospital; Oncology	Nottingham
United Kingdom	Peterborough City Hospital; Oncology Ward	Peterborough
United Kingdom	Queen Alexandra Hospital, Portsmouth	Portsmouth
United Kingdom	Weston Park Hospital; Cancer Clinical Trials Centre	Sheffield
United Kingdom	Southampton General Hospital; Somers Cancer Research Building	Southampton
United Kingdom	Uni Hospital of North Staffordshire; Staffordshire Oncology Centre	Stoke-on-Trent
United Kingdom	Royal Marsden Hospital; Dept of Medical Oncology	Sutton
United States	The Don & Sybil Harrington Cancer Center; Department of Clinical Research	Amarillo	Texas
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	Innovative Medical Research of South Florida	Aventura	Florida
United States	Mountain States Tumor Inst.	Boise	Idaho
United States	Boston Medical Center	Boston	Massachusetts
United States	Charleston Oncology, P .A	Charleston	South Carolina
United States	Medical University of SC (MUSC)	Charleston	South Carolina
United States	Carolinas Hem-Oncology Assoc	Charlotte	North Carolina
United States	SCRI Tennessee Oncology Chattanooga	Chattanooga	Tennessee
United States	Uni of Chicago	Chicago	Illinois
United States	Oncology Hematology Care - SCRI	Cincinnati	Ohio
United States	South Carolina Oncology Associates - SCRI	Columbia	South Carolina
United States	Northwest Oncology/ Hematology Assoc.	Coral Springs	Florida
United States	Uni of Texas Southwestern Medical Center	Dallas	Texas
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	The Providence Regional Medical Center Everett	Everett	Washington
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	San Juan Oncology Associates	Farmington	New Mexico
United States	Florida Cancer Specialists; SCRI	Fort Myers	Florida
United States	Queens Medical Associates	Fresh Meadows	New York
United States	West Clinic	Germantown	Tennessee
United States	Spectrum Health Grand Rapids	Grand Rapids	Michigan
United States	Hackensack Uni Medical Center; Northern Nj Cancer Center	Hackensack	New Jersey
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Carolina Oncology Specialists, PA - Hickory	Hickory	North Carolina
United States	Cancer Research Center of Hawaii; Clinical Sciences	Honolulu	Hawaii
United States	Uni of Texas - Md Anderson Cancer Center; Dept of Breast Medical Oncology	Houston	Texas
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Mayo Clinic-Jacksonville	Jacksonville	Florida
United States	Queens Hospital Center	Jamaica	New York
United States	Scripps Cancer Center	La Jolla	California
United States	University of California; Moores Cancer Center	La Jolla	California
United States	Horizon Oncology Research, Inc.	Lafayette	Indiana
United States	Arena Oncology Associates	Lake Success	New York
United States	Dartmouth Hitchcock Med Center	Lebanon	New Hampshire
United States	Uni of Arkansas For Medical Sciences; Arkansas Cancer Research Center	Little Rock	Arkansas
United States	James Graham Brown Cancer Center, University of Louisville	Louisville	Kentucky
United States	Loyola University Med Center	Maywood	Illinois
United States	Uni of Miami School of Medicine; Sylvester Comprehensive Cancer Center	Miami	Florida
United States	University of Minnesota.	Minneapolis	Minnesota
United States	Clnc L Trials & Rsch Assoc-Inc	Montebello	California
United States	Tennessee Onc., PLLC - SCRI	Nashville	Tennessee
United States	Vanderbilt-Ingram Cancer Ctr	Nashville	Tennessee
United States	Cancer Inst. of New Jersey	New Brunswick	New Jersey
United States	Smilow Cancer Hospital at Yale New Haven	New Haven	Connecticut
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Weill Medical College of Cornell Uni	New York	New York
United States	Northern Utah Associates	Ogden	Utah
United States	Illinois Cancer Care	Peoria	Illinois
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	St. John'S Mercy Medical Center; David C. Pratt Cancer Center	Saint Louis	Missouri
United States	Southern California Kaiser Permanente	San Diego	California
United States	Breastlink Medical Group Inc	Santa Ana	California
United States	New England Cancer Specialists	Scarborough	Maine
United States	University of Washington	Seattle	Washington
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Mercy Clinic Cancer & Hematology	Springfield	Missouri
United States	Northwest Medical Specialties	Tacoma	Washington
United States	Kaiser Permanente; Oncology Clinical Trials	Vallejo	California
United States	Marion L. Shepard Cancer Center	Washington	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Hoffmann-La Roche	Genentech, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Bahamas,  Belgium,  Bosnia and Herzegovina,  Brazil,  Canada,  Colombia,  Czechia,  Denmark,  France,  Germany,  Greece,  Guatemala,  Hungary,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Mexico,  New Zealand,  North Macedonia,  Panama,  Peru,  Philippines,  Poland,  Portugal,  Romania,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment	Tumor assessments were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a greater than or equal to (=) 20 percent (%) and 5-millimeter (mm) increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Primary	Progression-Free Survival (PFS) According to IRF Assessment	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a =20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants Who Died Prior to Clinical Cutoff	The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.	Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Secondary	Overall Survival (OS) at Clinical Cutoff	OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.	Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Secondary	Percentage of Participants With Death or Disease Progression According to Investigator Assessment	Tumor assessments were performed by the investigator according to RECIST version 1.1. Disease progression was defined as a =20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	PFS According to Investigator Assessment	Tumor assessments were performed by the investigator according to RECIST version 1.1. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a =20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants Experiencing Treatment Failure	Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. The percentage of participants with treatment failure was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Secondary	Time to Treatment Failure (TTF)	Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. TTF was defined as the time from randomization to treatment failure. Median TTF was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Secondary	One-Year Survival Rate	The percentage of participants alive at 1 year after randomization was estimated as the one-year survival rate using Kaplan-Meier analysis, and corresponding CIs were computed using Greenwood's estimate of the standard error.	From randomization until 1 year
Secondary	Percentage of Participants With Grade =3 Adverse Events	Adverse events were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival. Grade 5: Death.	Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose
Secondary	Percentage of Participants Who Died at 2 Years		From randomization until 2 years
Secondary	Overall Survival Truncated at 2 Years	Overall Survival truncated at 2 years was defined as the percentage of participants alive at 2 years.	From randomization until 2 years
Secondary	Percentage of Participants With Grade 5 Adverse Events	Adverse events were graded according to NCI CTCAE version 4.0. Grade 5 adverse events are those events which led to death.	Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose)
Secondary	Percentage of Participants With Grade 3-4 Laboratory Parameters	Laboratory results were graded according to NCI CTCAE version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival.	Day 1, 8, and 15 of Cycle 1-3 and on Day 1 of each subsequent cycle up to 50 months from randomization until clinical cutoff of 16-Sept-2014
Secondary	Percentage of Participants With Decline of =2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status	The ECOG performance status is a scale used to quantify cancer participants' general well-being and activities of daily life. The scale ranges from 0 to 5, with 0 denoting perfect health and 5 indicating death. The 6 categories are 0=Asymptomatic (Fully active, able to carry on all predisease activities without restriction), 1=Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2=Symptomatic, < 50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3=Symptomatic, > 50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4=Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair), 5=Death.	Baseline, Day 1 of every Cycle up to Clinical Data Cut (up to 48 months)
Secondary	Hospitalization Days	Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment. Reported values represent number of days admitted per participants.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Secondary	Percentage of Participants With Hospitalization	Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Secondary	Percentage of Participants With Objective Response According to IRF Assessment	Objective response was defined as having complete response (CR) or partial response (PR), assessed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a =30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the objective response rate [ORR]) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.	Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants With Objective Response According to Investigator Assessment	Objective response was defined as having CR or PR, assessed according to RECIST version 1.1, by investigator. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a =30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.	Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Duration of Response According to IRF Assessment	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Duration of response was defined as the time from confirmed PR or CR to first documented disease progression or death from any cause. CR was defined as the disappearance of all target lesions and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a =30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. Median duration of response was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.	Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a =30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient (20%) increase to qualify for disease progression. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR, PR, or SD was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.	Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants Experiencing a Clinically Significant Increase in Taxane-Related Treatment Symptoms as Measured by Taxane Subscale of the Functional Assessment of Cancer Therapy (FACT) Taxane (FACT-TaxS) Score	The FACT-Taxane is a self-reported instrument which measures the health-related quality of life (HRQOL) of participants receiving taxane-containing chemotherapy. The FACT-TaxS consists of 16 items including 11 neurotoxicity-related questions and 5 additional questions assessing arthralgia, myalgia, and skin discoloration. Items are rated from 0 (not at all) to 4 (very much) and a total score is inversely derived. Scores may range from 0 to 64, with higher scores indicating fewer/no symptoms. A minimally clinically important difference in treatment-related symptoms was defined as a =5% decrease (ie, 3.2 points) in FACT-TaxS score from Baseline. The percentage of participants with treatment-related symptoms was calculated using following formula: [number of participants meeting the above threshold divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.	Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module	The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with nausea was calculated using following formula: [number of participants with any level of either symptom divided by the number analyzed] multiplied by 100.	At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
Secondary	Percentage of Participants Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module	The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with diarrhea was calculated using following formula: [number of participants with any level of either symptom divided by the number analyzed] multiplied by 100.	At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
Secondary	Percentage of Participants With a Clinically Significant Deterioration in Health Related Quality of Life (HRQoL) as Measured by FACT Breast (FACT-B) Trial Outcome Index-Physical Function Breast (TOI-PFB) Score	The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. The percentage of participants with deterioration was calculated as [number of participants meeting the above threshold divided by the number analyzed] multiplied by 100.	Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
Secondary	Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score	The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including PWB, SWB, EWB, FWB, and BCS. The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. Time to deterioration was defined as the time from Baseline until the first decrease in FACT-B TOI-PFB score. Median time to deterioration was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.	Baseline up to 39 months from randomization until clinical cutoff of 16-Sept-2014
Secondary	Change From Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score	The RSCL is a self-reported instrument which consists of 4 domains including physical symptom distress, psychological distress, activity level, and overall global life quality. Only the activity level scale was collected and assessed. Scores may range from 0 to 100, with higher scores indicating increased burden of disease. Mean RSCL activity scale score changes were calculated as [mean score at the assessment visit minus mean score at Baseline]. The higher the score, the higher the level of impairment or burden.	Baseline, Cycle 7 (Week 18)
Secondary	Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score	The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of participants reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect)	Baseline, Cycle 7 (Week 18)
Secondary	Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score	The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of participants reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect).	Baseline, Cycle 7 (Week 18)
Secondary	Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With High Human Epidermal Growth Factor Receptor 2 (HER2) Messenger Ribonucleic Acid (mRNA) Levels	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a =30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.	Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a =30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.	Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a =20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	PFS According to IRF Assessment Among Those With High HER2 mRNA Levels	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a =20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a =20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels	Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a =20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis.	Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Secondary	Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels	The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.	Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Secondary	OS at Clinical Cutoff Among Those With High HER2 mRNA Levels	OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis.	Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Secondary	Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels	The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.	Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Secondary	OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels	OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis. Reported upper bound of confidence interval for "Trastuzumab Emtansine + Placebo" and confidence interval values for "Trastuzumab + Taxane" and "Trastuzumab Emtansine + Pertuzumab" are censored values.	Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)