A Study of a Combination of Trastuzumab and Capecitabine With or Without Pertuzumab in Patients With HER2-positive Metastatic Breast Cancer (PHEREXA)

Breast Cancer Clinical Trial

Official title:

A Multicenter Randomized Phase III Study to Compare the Combination Trastuzumab and Capecitabine, With or Without Pertuzumab, in Patients With HER2-Positive Metastatic Breast Cancer That Have Progressed After One Line of Trastuzumab-Based Therapy in the Metastatic Setting (PHEREXA)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01026142
• Other study ID #: MO22324
• Secondary ID: 2008-006801-17
• Status: Completed
• Phase: Phase 3
• Start date: January 26, 2010
• Est. completion date: August 7, 2017

Study information

• Verified date: July 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized, two-arm study evaluated the efficacy and safety of a combination of trastuzumab and capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The study population consisted of female patients, whose disease had progressed during or following previous trastuzumab therapy for metastatic disease. All patients in Arm A and Arm B received trastuzumab (8 mg/kg iv as loading dose and then 6 mg/kg iv every 3 weeks thereafter) and capecitabine oral twice daily for 14 days every 3 weeks (1250 mg/m2 twice daily in Arm A and 1000 mg/m2 twice daily in Arm B). In addition, patients in Arm B received pertuzumab (840 mg iv as loading dose and then 420 mg iv thereafter) every 3 weeks. Study treatment continued until disease progression or unacceptable toxicity.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 452
• Est. completion date: August 7, 2017
• Est. primary completion date: May 29, 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult female patients >/=18 years of age

• Metastatic HER2 positive breast cancer

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Disease progression during or following trastuzumab-based therapy for 1st line metastatic breast cancer (trastuzumab must have been part of the last prior treatment regimen)

• Prior treatment with taxane-containing regimen

• Left ventricular ejection fraction (LVEF) >/=50 percent

• For women of childbearing potential agreement to use highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by patient and/or partner. Contraception must continue for duration of study treatment and for at least 6 months after last dose of study drug treatment

Exclusion Criteria:

• Prior treatment with pertuzumab or capecitabine

• Concurrent treatment with other experimental drug

• Concurrent immunotherapy or anticancer hormonal therapy

• Serious concurrent disease (e.g. active infection, uncontrolled hypertension, cardiovascular disease)

• Central nervous system (CNS) metastases, which are not well controlled

• History of exposure to anthracycline cumulative dose equivalent to 360mg/m2

• History of congestive heart failure of any New York Heart Association criteria, or serious cardiac arrhythmia requiring treatment

• History of myocardial infarction within 6 months prior to randomization

• History of LVEF decline to below 50% during or after prior trastuzumab therapy or other cardiac toxicity during previous trastuzumab treatment that necessitated discontinuation of trastuzumab

• History of another cancer which could affect compliance or result interpretation

• Inadequate organ function

• Pregnant or breastfeeding women

• life expectancy < 12 weeks

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Capecitabine
1000 mg/m2 po twice daily for 14 days every 3 weeks
• Capecitabine
1250 mg/m2 po twice daily for 14 days every 3 weeks
• Pertuzumab
840 mg iv loading, then 420 mg iv every 3 weeks
• Trastuzumab
8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks

Locations

Country	Name	City	State
Argentina	Fundación Investigar	Buenos Aires
Argentina	Hospital Britanico; Oncologia	Buenos Aires
Argentina	Instituto FIDES	La Plata
Argentina	Instituto de Investigaciones Clínicas Quilmes	Quilmes
Argentina	Instituto de Oncología de Rosario	Rosario
Argentina	ISIS Clinica Especializada	Santa Fe
Austria	A.Ö. Landesschwerpunktkrankenhaus Krems; Abtl. F. Innere Med.	Krems
Austria	Landeskrankenhaus Rankweil; Interne E	Rankweil
Austria	Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.	Salzburg
Austria	Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie	Wien
Belgium	Imeldaziekenhuis	Bonheiden
Belgium	AZ KLINA	Brasschaat
Belgium	UZ Brussel	Brussel
Belgium	GHdC Site Notre Dame	Charleroi
Belgium	CH Jolimont - Lobbes (Jolimont)	Haine-Saint-Paul
Belgium	Jessa Zkh (Campus Virga Jesse)	Hasselt
Belgium	AZ Groeninge	Kortrijk
Belgium	CHU Sart-Tilman	Liège
Belgium	Clinique Saint-Joseph	Liège
Belgium	Clinique Ste-Elisabeth	Namur
Belgium	AZ Nikolaas (Lodewijk)	Sint-Niklaas
Brazil	Oncologia Sul Capixaba Servicos Medicos - Oncosul	Cachoeiro Do Itapemirim	ES
Brazil	Hospital Sao Lucas - PUCRS	Porto Alegre	RS
Brazil	Hospital A. C. Camargo; Oncologia	Sao Paulo	SP
Brazil	Hospital Perola Byington	Sao Paulo	SP
Brazil	Centro Oncológico de Mogi das Cruzes	São Paulo- SP	SP
Canada	Durham Regional Cancer Centre	Oshawa	Ontario
Canada	Humber River Hospital	Toronto	Ontario
Canada	University Health Network; Princess Margaret Hospital; Medical Oncology Dept	Toronto	Ontario
Croatia	Uni Hospital For Tumours; Dept of Medical Oncology	Zagreb
Czechia	Masarykuv onkologicky ustav; Oncology II	Brno
Czechia	University Hospital; Oncology and Radiotherapy	Hradec Kralove
Czechia	Lekarske Fakulty Univerzity Karlovy Fakultni Nemocnice Na Bulovce; Ustav Radiacni Onkologie	Praha
Czechia	Fakultni Poliklinika Vseobecne Fakultni Niemocnice; Onkologicka Klinika	Praha 2
Estonia	North Estonia Medical Centre Foundation; Oncology Centre	Tallinn
Estonia	Tartu University Hospital; Clinic of Hematology and Oncology	Tartu
France	C.H. Du Pays D'aix En Provence Service du Dr Blanc	Aix En Provence
France	Centre Oncologie Du Pays Basque	Bayonne
France	Centre Hospitalier Fleyriat; Oncologie/Hematologie	Bourg En Bresse
France	CHU Henri Mondor; Service d'Oncologie Medicale	Creteil
France	Centre Georges Francois Leclerc; Oncologie 3	Dijon
France	Centre Leon Berard; Oncologie Genetique	Lyon
France	Centre Antoine Lacassagne; Hopital De Jour A2	Nice
France	Hopital Saint Antoine; Sce Oncologie	Paris
France	Institut Curie; Oncologie Medicale	Paris
France	Institut Jean Godinot; Oncologie Medicale	Reims CEDEX
France	Centre Henri Becquerel; Oncologie Medicale	Rouen
France	Centre Rene Huguenin; CONSULT SPECIALISEES	St Cloud
France	Hopital Hautepierre; Hematologie Oncologie	Strasbourg
France	Clinique Pasteur; Oncologie Medicale	Toulouse
France	Institut Claudius Regaud; Departement Oncologie Medicale	Toulouse
Germany	CAMPUS CHARITÉ MITTE; Tagesklinik für Onkologie u.Hämatologie	Berlin
Germany	Klinikum Sindelfinden Boblingen	Böblingen
Germany	Klinikum Bremen-Mitte gGmbH; Frauenklinik	Bremen
Germany	Klinikum Darmstadt GmbH; Med. Klinik V; Onkologie & Hämatologie	Darmstadt
Germany	Klinikum Dortmund gGmbH Klinikzentrum Mitte	Dortmund
Germany	Universitätsklinikum Essen; Zentrum Für Frauenheilkunde	Essen
Germany	Klinikum Frankfurt Höchst GmbH; Klinik für Gynäkologie und Geburtshilfe	Frankfurt
Germany	Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH	Fulda
Germany	HOPA MVZ GmbH	Hamburg
Germany	Universitätsklinikum Hamburg-Eppendorf; Zentrum für operative Medizin Klinik für Gynäkologie	Hamburg
Germany	Diakovere Henriettenstift, Frauenklinik	Hannover
Germany	Medizinische Hochschule Zentrum Frauenheilkunde Abt.Gynäkologische Onkologie	Hannover
Germany	ViDia Christliche Kliniken Karlsruhe, Vincentius-Diakonissen-Kliniken gAG; Frauenklinik	Karlsruhe
Germany	Systemedic Frauenarzte Pruener Gang	Kiel
Germany	Institut für Versorgungsforschung in der Onkologie GbR Koblenz	Koblenz
Germany	St. Elisabeth Krankenhaus Köln GmbH; Gynäkologie und Geburtshilfe	Koeln
Germany	Universitätsklinikum Schleswig-Holstein / Campus Lübeck; Klinik für Frauenheilkunde und Geburtshilfe	Lübeck
Germany	St. Vincenz-Elisabeth-Hospital; Katholisches Klinikum Mainz	Mainz
Germany	Klinikum rechts der Isar der TU München; Frauenklinik & Poliklinik	München
Germany	Universitätsklinikum Münster; Klinik für Frauenheilkunde und Geburtshilfe	Münster
Germany	St. Josefs Klinik; Medizinische Klinik	Offenburg
Germany	Praxis für Onkologie und Hämatologie	Recklinghausen
Germany	Johanniter Klinik	Stendal
Germany	Klinikum Mutterhaus der Borromaeerinnen gGmbH; Haematologie/Onkologie	Trier
Germany	GRN Klinik Weinheim	Weinheim
Hong Kong	Queen Elizabeth Hospital; Clinical Oncology	Hong Kong
Hong Kong	Queen Mary Hospital; Surgery	Hong Kong
Hong Kong	Tuen Mun Hospital; Clinical Oncology	Hong Kong
Hungary	Fövárosi Önkormányzat Bajcsy-Zsilinszky Kórház; Onkológiai Osztály	Budapest
Hungary	Municipal Hospital of Uzsoki Utca; Centre of Oncoradiology	Budapest
Hungary	Ogyi, Orszagos Gyogyszereszeti Intezet	Budapest
Hungary	Orszagos Onkologiai Intezet; B Belgyogyaszati Osztaly	Budapest
Hungary	Semmelweis Egyetem Aok; Iii.Sz. Belgyogyaszati Klinika	Budapest
Hungary	Semmelweis Egyetem Onkologiai Központ	Budapest
Hungary	Hospital of Aladar Petz; Dept of Oncoradiology	Gyor
Hungary	Békés Megyei Pándy Kálmán Kórház; Onkologiai tanszek	Gyula
Hungary	Kaposi Mor County Hospital; Dept. of Oncology	Kaposvar
Hungary	Borsod-Abauj-Zemplen Megyei Korhaz Es Egyetemi Oktato Korhaz; Onkologiai Osztaly	Miskolc
Hungary	Josa Andras Korhaz; Dept of Oncoradiology	Nyíregyháza
Hungary	Pécsi Tudományegyetem Áok; Onkoterapias Intezet	Pecs
Hungary	Szegedi Tudomanyegyetem, AOK, Szent-Gyorgyi Albert Klinikai Kozpont, Onkoterapias Klinika	Szeged
Hungary	Fejér Megyei Szent György Kórház; Onkológiai Osztály	Szekesfehervar
Hungary	Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház; Onkológiai Osztály	Szolnok
Italy	Asst Papa Giovanni XXIII; Oncologia Medica	Bergamo	Lombardia
Italy	Az. Osp. S. Orsola Malpighi; Istituto Di Oncologia Seragnoli	Bologna	Emilia-Romagna
Italy	Ospedale Cervesi di Cattolica ; Unità Operativa di Oncologia ed Oncoematologia	Cattalica	Emilia-Romagna
Italy	AUSL Cesena; Servizio di Oncologia	Cesena	Emilia-Romagna
Italy	ASST DI CREMONA; Dipartimento Aziendale Oncologico	Cremona	Lombardia
Italy	Ausl Ravenna-Osp.Infermi; Day Hospital Oncologia Medica	Faenza	Emilia-Romagna
Italy	Azienda ospedaliero-universitaria careggi, Sezione di radioterapia del dipartimento di fisiopatolo	Firenze	Toscana
Italy	Ospedale Mater Salutis; Dept of Oncology	Legnago	Lombardia
Italy	Ospedale Umberto I ASL di Ravenna Presidio Ospedaliero di Lugo	Lugo	Emilia-Romagna
Italy	ASST DI MONZA; Oncologia Medica	Monza	Lombardia
Italy	Istituto Tumori Fondazione Pascale; Endocrinologia Oncologica	Napoli	Campania
Italy	ARNAS-Ospedale Civico Maurizio Ascoli; Unità Operativa di Oncologia Medica	Palermo	Sicilia
Italy	IRCCS Fondazione Maugeri; Oncologia Medica II	Pavia	Lombardia
Italy	A.O. Universitaria Pisana; Oncologia	Pisa	Toscana
Italy	Azienda USL di Ravenna; Unità Operativa di Oncologia Medica	Ravenna	Emilia-Romagna
Italy	Ospedale Infermi Di Rimini; Unità Operativa di Oncologia e Oncoematologia	Rimini	Emilia-Romagna
Italy	Istituto Regina Elena; Oncologia Medica A	Roma	Lazio
Italy	Uni Cattolica Policlinico Gemelli; Oncologia Medica Ist. Medicina Interna	Roma	Lazio
Italy	ASST LARIANA; Oncologia	S. Fermo Della Battaglia (CO)	Lombardia
Italy	Ospedale Civile; Oncologia Medica	Sassari	Sardegna
Italy	A.O. Città della Salute e della Scienza - Presidio Molinette; divisione oncologia medica	Torino	Piemonte
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	Seoul National University Hosp; Dept Internal Med Hem Onc	Seoul
Korea, Republic of	Severance Hospital	Seoul
Mexico	Oaxaca Site Management Organization	Oaxaca
Mexico	Centro Oncológico Estatal; ISSSEMYM Oncología	Toluca
Netherlands	Vu Medisch Centrum; Afdeling Maag-, Darm- En Leverziekte	Amsterdam
Peru	Hospital Nacional Carlos Alberto Seguin Escobedo-Essalud; Oncology & Haemathology	Arequipa
Peru	Hospital Nacional Edgardo Rebagliati Martins	Jesus Maria
Peru	Clinica Anglo Americana - Centro de Investigacion Oncologia CAA	Lima
Peru	Unidad de Investigacion Oncologia Clinica - Piura; Unidad de Oncología Clínica	Piura
Poland	Szpital Specjalistyczny Podkarpacki Osrodek Onkologiczny	Brzozów
Poland	Wojewodzki Szpital Zespolony; Oddzial Chemioterapii	Elblag
Poland	Wojewodzkie Centrum Onkologii	Gdansk
Poland	COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej	Lublin
Poland	Wojewodzki Sziptal Specjalistyczny Im. Janusza Korczaka; Oddzial Onkologiczny, Oddzial Chemioterapii	Slupsk
Romania	Institute Of Oncology Bucharest; Medical Oncology	Bucharest
Romania	Spitalul Clinic Sf. Maria; Departmental De Oncologie	Bucharest
Romania	Institut of Oncology Al. Trestioreanu Bucharest; Oncology Department	Bucuresti
Romania	Prof. Dr. I. Chiricuta Institute of Oncology	Cluj Napoca
Romania	Cluj Clinical County Hospital; Oncology Dept	Cluj-Napoca
Romania	Medisprof SRL	Cluj-Napoca
Romania	Municipal Clinical Hospital Filantropia; Oncology	Craiova
Romania	Euroclinic Center of Oncology SRL	Iasi
Russian Federation	Regional Oncology Hospital of Krasnodar; Oncology	Krasnodar
Russian Federation	Blokhin Cancer Research Center; Combined Treatment	Moscow
Russian Federation	Semashko Central Clinical Hospital; Dept of Chemotherapy	Moscow
Russian Federation	GUZ Perm Region Oncology Dispensary	Perm
Russian Federation	S.-Peterburg Pavlov State Medical University ; Haematology	St Petersburg
Russian Federation	Saint-Petersburg City Clinical Oncology Dispensary	St Petersburg
Russian Federation	SBI of Healthcare of Stavropol region Stavropol Regional Clinical Oncology Dispensary	Stavropol
Spain	Fundacion Hospital de Alcorcon; Servicio de Oncologia	Alcorcon	Madrid
Spain	Complejo Hospitalario Torrecardenas; Servicio de Oncologia	Almería	Almeria
Spain	Hospital Clinic i Provincial; Servicio de Farmacia	Barcelona
Spain	Institut Catala d Oncologia Hospital Duran i Reynals	Barcelona
Spain	Hospital Clinica Benidorm	Benidorm	Alicante
Spain	Hospital de Basurto; Servicio de Oncologia	Bilbao	Vizcaya
Spain	Hospital Provincial de Castellón	Castellon
Spain	Hospital Juan Ramon Jimenez;Servicio de Oncologia	Huelva
Spain	Hospital Universitario de Canarias;servicio de Oncologia	La Laguna	Tenerife
Spain	Complejo Asistencial Universitario de Leon; Servicio de Oncologia	Leon
Spain	Fundacion Jimenez Diaz; Servicio de Oncologia	Madrid
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid
Spain	Hospital La Paz	Madrid
Spain	Hospital Ruber Internacional;Servicio de Oncologia	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda	Madrid
Spain	Complejo Hospitalario de Pontevedra; Servicio de Oncologia	Pontevedra
Spain	Hospital de Sagunto; Servicio de Oncologia	Sagunto	Valencia
Spain	Hospital Clinico Universitario de Salamanca; Servicio de Oncologia	Salamanca
Spain	Complejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Oncologia	Santa Cruz de Tenerife	Tenerife
Spain	Hospital Univ. Nuestra Señora de Valme;	Sevilla
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitario Virgen Macarena; Servicio de Oncologia	Sevilla
Spain	Hospital Sant Pau i Santa Tecla	Tarragona
Spain	Consorci Hospitalari de Terrassa	Terrassa	Barcelona
Spain	Complejo Hospitalario de Toledo- H. Virgen de la Salud; Servicio de Oncologia	Toledo
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
Spain	Hospital Universitario la Fe; Servicio de Oncologia	Valencia
Spain	Instituto Valenciano Oncologia; Oncologia Medica	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza
Thailand	Phramongkutklao Hospital;Dept Surgery/Surgical Oncology Unit	Bangkok
Thailand	Ramathibodi Hospital; Department of Surgery/Breast and Endocrine Unit	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Hospital; Department of Surgery/Head Neck and Breast Unit; Clinical Trial	Chiang Mai
Thailand	Srinagarind Hospital; Department of Surgery	Khon Kaen
Thailand	Songklanagarind Hospital; Department of Surgery	Songkla
United Kingdom	Royal Bournemouth General Hospital; Oncology	Bournemouth
United Kingdom	Velindre Cancer Centre; Oncology Dept	Cardiff
United Kingdom	Broomfield Hospital	Chelmsford
United Kingdom	University Hospital of North Durham; Oncology	Durham
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Christie Hospital; Breast Cancer Research Office	Manchester
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Peterborough City Hospital, Edith Cavell Campus; Oncology Department	Peterborough
United Kingdom	Great Western Hospital; Clinical Oncology	Swindon
United Kingdom	Royal Cornwall Hospital; Dept of Clinical Oncology	Truro

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Argentina,  Austria,  Belgium,  Brazil,  Canada,  Croatia,  Czechia,  Estonia,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Peru,  Poland,  Romania,  Russian Federation,  Spain,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (Independent Assessment)	Progression Free Survival (PFS) was defined as the time from randomization to first documented disease progression (PD), as determined by an Independent Review Facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. IRF review of tumor assessment ceased after the primary PFS analysis. The primary endpoint was analyzed after approximately 337 IRF-assessed PFS events were observed.	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).
Secondary	Overall Survival (OS)	Overall Survival (OS) was defined as the time from the date of randomization to the date of death from any cause. The results of the final OS analysis are presented here. Participants who were alive or lost to follow-up at the time of the analysis were censored at the last known alive date. Participants with no postbaseline information were censored at the time of randomization plus 1 day. Prior to the final data analysis cut-off, it was ensured that all participants who were in survival follow-up had been contacted as recently as possible within the last 3 months to confirm current survival status.	From randomization until death from any cause (up to 7.5 years).
Secondary	Overall Survival (OS) Rate Based on a 2-year Truncated Analysis	The Overall Survival (OS) 2-year truncated analysis is the Kaplan-Meier estimate of the percentage of participants who were surviving at 2 years. OS is defined as the time from the date of randomization to the date of death from any cause, with censoring of all events and follow-up beyond the end of the second year.	From randomization until death from any cause (up to 2 years)
Secondary	Investigator Assessment Progression-Free Survival (PFS)	Investigator Assessment Progression-Free Survival (PFS) was defined as the time from randomization to the first documented progressive disease, as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0, or death from any cause, whichever occurred first. PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 7.5 years).
Secondary	Time to Progression (TTP) Based Upon Independent Review Facility (IRF) Assessment	Time to Progression (TTP) was defined as time between randomization and the first occurrence of progressive disease (PD), based on IRF assessment.	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).
Secondary	Time to Treatment Failure (TTF) Based Upon Independent Review Facility (IRF) Assessment	Time to Treatment Failure (TTF) was defined as time between randomization and date of disease progression based on independent review, death, or withdrawal of treatment due to adverse events, withdrawn informed consent, refusal of treatment/failure to cooperate, or failure to return, whichever occurred first.	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).
Secondary	Overall Objective Response Rate (ORR)	Overall Objective Response Rate is based upon investigator and IRF assessments. Objective Response Rate (ORR) was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) among those who had measurable disease at baseline. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).
Secondary	Clinical Benefit Rate (CBR)	Clinical Benefit Rate is based upon Independent Review Facility (IRF) assessments; defined as the percentage of participants a complete response (CR), partial response (PR), or stable disease for at least 8 cycles or 6 months.	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).
Secondary	Duration of Objective Response	Duration of Objective Response was defined for the subpopulation of responders as time from first Independent Review Facility (IRF)-assessed complete response (CR) or partial response (PR) to subsequent first documented, IRF-confirmed evidence of disease progression. Only participants with an objective response were included in the analysis of duration of objective response.	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).