Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin Versus CAV or Topotecan as Treatment in Patients With Small-Cell Lung Cancer

Small-cell Lung Cancer Clinical Trial

— ATLANTIS  

Official title:

Phase III Randomized Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin Versus Cyclophosphamide, Doxorubicin and Vincristine (CAV) or Topotecan as Treatment in Patients With Small-Cell Lung Cancer (SCLC) Who Failed One Prior Platinum-containing Line (ATLANTIS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02566993
• Other study ID #: PM1183-C-003-14
• Status: Completed
• Phase: Phase 3
• Start date: August 30, 2016
• Est. completion date: February 24, 2020

Study information

• Verified date: August 2021
• Source: PharmaMar
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase III randomized clinical trial of lurbinectedin (PM01183)/doxorubicin (DOX) versus cyclophosphamide (CTX), doxorubicin (DOX) and vincristine (VCR) (CAV) or topotecan as treatment in patients with small-cell lung cancer (SCLC) who failed one prior platinum-containing line.

Description:

Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate and compare the activity and safety of an experimental arm consisting of PM01183/DOX combination followed by PM01183 alone, if applicable vs. best Investigator's choice between CAV or topotecan as a control arm, in SCLC patients who failed one prior platinum-containing line but no more than one prior chemotherapy-containing line.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 613
• Est. completion date: February 24, 2020
• Est. primary completion date: February 24, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Voluntary written informed consent

2. Adult patients = 18 years

3. Histologically or cytologically confirmed diagnosis of limited or extensive stage SCLC which failed one prior platinum-containing regimen and with a chemotherapy-free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease) = 30 days. Small-cell carcinoma of unknown primary site with or without neuroendocrine features confirmed in histology test(s) performed on metastatic lesion(s) are eligible, if Ki-67/MIB-1 is expressed in >50% of tumor cells.

4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 2.

5. Adequate hematological, renal, metabolic and hepatic function within 7-10 days prior to randomization

6. At least three weeks since last prior anticancer treatment and adequate recovery from prior treatment toxicity

7. Prior radiotherapy (RT): At least four weeks since completion of whole-brain irradiation, at least two weeks since completion of prophylactic cranial irradiation, and to any other site.

8. Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six weeks after treatment discontinuation. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product dose.

Exclusion Criteria:

1. More than one prior chemotherapy-containing line(re-challenge with the same initial regimen is not allowed)

2. Patients who never received platinum-containing regimen for Small-cell Lung Cancer (SCLC)

3. Prior treatment with PM01183, topotecan or anthracyclines.

4. Limited-stage patients who are candidates for local or regional therapy

5. Impending need for palliative RT or surgery for pathological fractures and/or for medullary compression within four weeks prior to randomization.

6. Symptomatic or progressing or steroid requiring Central Nervous System (CNS) involvement disease at least four weeks prior to randomization

7. Concomitant diseases/conditions:

Angina, myocardial infarction, congestive heart failure or clinically significant valvular heart disease, arrhythmia, immunodeficiency (including known HIV seropositive), ongoing or treatment-requiring chronic liver disease, active infection, oxygen requirement within two weeks prior to randomization, diffuse interstitial lung disease (ILD) or pulmonary fibrosis, second invasive malignancy treated with chemotherapy and/or radiotherapy, invasive fungal infections requiring systemic treatment within 12 weeks of randomization.

8. Pregnant or breast feeding women

Related Conditions & MeSH terms

• Lung Neoplasms
• Small Cell Lung Carcinoma
• Small-cell Lung Cancer

Intervention

Drug:
• Lurbinectedin (PM01183)

• Doxorubicin (DOX)

• Cyclophosphamide (CTX)

• Vincristine (VCR)

• Topotecan

Locations

Country	Name	City	State
Argentina	Instituto Médico Especializado Alexander Fleming	C.a.b.a.	Buenos Aires
Argentina	Instituto Oncológico de Córdoba (IONC)	Córdoba
Argentina	CORI - Centro Oncológico Riojano Integral	La Rioja
Argentina	Centro para la Atención Integral del Paciente Oncológico (CAIPO)	San Miguel de Tucumán	Tucumán
Argentina	ISIS Centro Especializado de Luce S.A.	Santa Fe
Austria	Universitätsklinik für Innere Medizin III der PMU	Salzburg
Austria	Medizinische Universität Wien / AKH Wien, Universitätsklinik für Innere Medizin I, Abteilung für klinische Onkologie	Wien
Belgium	AZ Maria Middelares	Gent
Belgium	Clinique André Renard	Herstal
Belgium	CHR de la citadelle	Liege
Belgium	CHU de Liege - Sart Tilman	Liege
Belgium	CHU Ambroise Paré	Mons
Belgium	AZ Delta Campus Wilgenstraat	Roeselare
Brazil	Fundação PlO XII - Hospital de Câncer de Barretos	Barretos	São Paulo
Brazil	lOP- Instituto de oncologia do paraná	Curitiba	Paraná
Brazil	Associação Hospital de Caridade de Ijuí	Ijui	RS
Brazil	Hospital São Lucas da PUCRS	Porto Alegre	RS
Brazil	lrmandade da Santa Casa de Misericórdia de Porto Alegre	Porto Alegre	RS
Brazil	Hospital de clínicas de Porto alegre	Pôrto Alegre	RS
Brazil	Coordenação de Pesquisa Clínica / Instituto Nacional de Câncer	Rio de Janeiro	RJ
Brazil	Instituto COl de Pesquisa, Educação e Gestão	Rio de Janeiro	RJ
Brazil	Nucleo de Oncologia da Bahia	Salvador	BA
Brazil	lnstituto de Ensino e Pesquisa Säo Lucas - IEP Säo Lucas	Sao Paulo	São Paulo
Bulgaria	Multiprofile Hospital for Active Treatment - Uni Hospital, Panagyurishte	Panagyurishte
Bulgaria	Acibadem City Clinic University Multiprofile Hospital for Active Treatment. EOOD, Sofia; Clinic of Medical Oncology	Sofia
Bulgaria	Multiprofile Hospital for Active Treatment of Women Health - "Nadezhda", Sofia; Clinic of Medical Oncology	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment "Sv. Ivan Rilski", Sofia	Sofia
Canada	Centre intégré de santé et de services sociaux de la Montérégie Centre	Greenfield Park	Quebec
Canada	Biron (Clinique René Laennec)	Mont-Royal	Quebec
Canada	Montreal Oncology Research Inc.	Montreal	Quebec
Canada	McGill University Health Centre	Montréal	Quebec
Canada	Southlake Regional Health Centre - Stronach Regional Cancer Centre	Newmarket	Ontario
Canada	R.S. Mc Laughlin Durham Regional Cancer Centre, Lakeridge Health	Oshawa	Ontario
Czechia	Vitkovicka nemocnice, a.s., Plicni oddeleni	Ostrava
Czechia	Krajska zdravotni a.s. Masarykova nemocnice o.z.	Usti nad Labem
France	Institut Bergonié	Bordeaux
France	Centre François Baclesse	Caen
France	Centre Hospitalier Intercommunal de Créteil	Creteil
France	Centre Hospitalier Lyon Sud - Service de Pneumologie	Lyon
France	Hôpital Nord - Service Oncologie Multidisciplinaire et Innovations Thérapeutiques	Marseille
France	Centre Antoine Lacassagne	Nice Cedex 2
France	CHU de Rennes Hôpital Pontchaillou	Rennes
Germany	Central Clinic of Bad Berka	Bad Berka
Germany	Evangelische Lungenklinik Berlin	Berlin
Germany	Vivantes Klinikum am Urban, Hämatologie und Onkologie	Berlin
Germany	Uniklinik Freiburg, Hämatologie, Onkologie & Stammzellransplantation	Freiburg
Germany	Asklepios-Fachkliniken München Gauting	Gauting
Germany	Center for Pneumology and Thoracic Surgery	Gerlingen
Germany	Thoraxklinik Heidelberg GmbH	Heidelberg
Germany	Lungenklinik Hemer	Hemer
Germany	VIDIA Christliche Kliniken Karlsruhe	Karlsruhe
Germany	Katholisches Klinikum Koblenz-Montabaur, Marienhof Koblenz	Koblenz
Germany	Onkologische Schwerpunktpraxis Leer-Emden	Leer
Germany	Klinik Löwenstein gGmbH, Med. Klinik II Onkologie	Löwenstein
Germany	Uniklinikum Mannheim, TTZ, Medizinische Fakultät Mannheim	Mannheim
Germany	Johannes Wesling Klinikum Minden, Klinik für Hämatologie, Onkologie und Palliativmedizin	Minden
Germany	Klinikum Bogenhausen, Städt. Klinikum München GmbH, Klinik für Pneumologie und Pneumologische Onkologie	Munchen
Germany	Städtisches Krankenhaus München Neuperlach	Munchen
Germany	University of Munich LMU, Dpt. of Medicine V	Munchen
Germany	Klinikum Nürnberg Nord - Pneumologische Onkologie	Nuremberg
Germany	Universitätsklinikum Ulm - Klinik für Innere Medizin II, Pneumologie	Ulm
Germany	Medizinische Klinik I	Wuppertal
Greece	General Hospital of Chest Diseases of Athens "Sotiria"	Athens
Greece	General Oncology Hospital of Kifissia "Agioi Anargiroi", 2nd Internal Medicine-Oncology Clinic	Athens
Greece	University General Hospital of Heraklion - General Hospital "Venizeleio"	Heraklion	Crete
Greece	General Hospital of Thessaloniki "G. Papanikolaou", Pulmonary Clinic, Aristotle University of Thessaloniki	Thessaloniki
Hungary	Országos Korányi TBC és Pulmonológiai Intézet, 6. Pulmonológia és Bronchologia	Budapest
Hungary	Országos Korányi TBC és Pulmonológiai lntézet, 14. Pulmonológia	Budapest
Hungary	Veszprém Megyei Tüdögyógyintézet, 3. Pulmonológiai Osztály	Farkasgyepu
Hungary	Mátrai Gyógyintézet, Bronchológia	Matrahaza
Hungary	Miskolci Semmelweis Kórház és Egyetemi Oktatókórház, Pulmonológiai Osztály	Miskolc
Hungary	Fejér Megyei Szent György Egyetemi Oktató Kórház, I. Pulmonológiai Osztály	Szekesfehervar
Hungary	Markusovszky Egyetemi Oktatókórház, Pulmonológiai Osztály	Szombathely
Hungary	Szent Borbála Kórház, Pulmonológiai osztály	Tatabanya
Hungary	Zala Megyei Kórház, Pulmonologia	Zalaegerszeg
Italy	Centro di Riferimento Oncologico di Aviano	Aviano
Italy	Azienda Ospedaliero - Universitaria "Policlinico - Vittorio Emanuele" - Presidio G. Rodolico	Catania
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano	MI
Italy	AOU Maggiore della Carità - SC Oncologia	Novara
Italy	Istituto Oncologico Veneto	Padova
Italy	lRCCS-Arcispedale Santa Maria Nuova	Reggio Emilia
Italy	IRCCS CROB (Istituto di Ricovero e Cura a Carattere Scientifico)	Rionero in Vulture	PZ
Italy	Policlinico Universitario Campus Bio-Medico	Roma
Italy	ASST della Valtellina e dell' Alto Lario P.O. Di Sondrio	Sondrio
Lebanon	Ain Wazein Hospital	Ain Wazein	El Chouf
Lebanon	American University of Beirut Medical Center	Beirut
Lebanon	Hotel Dieu de France	Beirut
Lebanon	Centre Hospitalier Universitaire Notre Dame de Secours	Biblos
Lebanon	Hammoud Hospital University Medical Center	Sidon
Netherlands	The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital	Amsterdam
Netherlands	Spaarne Gasthuis	Hoofddorp
Netherlands	MUMC	Maastricht
Netherlands	Maxima Medisch Centrum	Veldhoven
Poland	Bialostockie Centrum Onkologii im. Marii Sklodowskiej-Curie; Oddzial Onkologii Klinicznej im. dr Ewy Pileckiej z pododdzialem	Bialystok
Poland	Szpitale Pomorskie Sp. z o.o., Oddzial Onkologii Klinicznej, Oddzial Onkologii i Radioterapii	Gdynia
Poland	Mazowieckie Centrum Leczenia Chorób Pluc i Gruzlicy Oddzial III Chorób Pluc z Pododdzialem Onkologicznym	Otwock
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. K.Marcinkowskiego w Poznaniu, Oddzial Chemioterapii	Poznan
Portugal	Centro Clínico Champalimaud - Fundação Champalimaud	Lisboa
Portugal	Centro Hospitalar Lisboa Norte, EPE- Hospital Pulido Valente	Lisboa
Portugal	Centro Hospitalar de São João, EPE	Porto
Portugal	Centro Hospitalar do Porto, EPE - Hospital de Santo António	Porto
Portugal	Hospital CUF Porto	Porto
Portugal	Instituto Português de Oncologia do Porto Francisco Gentil, EPE	Porto
Romania	Spitalul Judetean de Urgenta "Dr. Constantin Opris", Sectia Oncologie Medicala	Baia Mare	Maramures
Romania	Institutul Oncologic "Prof. Dr. Ion Chiricuta" Cluj-Napoca, Departament Oncologie Medicala	Cluj
Romania	Institutul Oncologic "Prof. Dr. lon Chiricuta" Cluj-Napoca, Dcpartamentul Oncologie Medicala	Cluj
Romania	Institutul Oncologic "Prof. Dr. lon Chiricuta" Cluj-Napoca, Sectia Oncologic Medicala	Cluj
Romania	Spitalul Clinic Judetean de Urgenta "Sf. Apostol Andrei"	Constanta	Judet Constanta
Romania	SC Centrul de Oncologie Sf. Nectarie SRL, Departament Oncologie Medícala	Craiova	Dolj
Romania	SC Oncolab SRL	Craiova	Judet Dolj
Spain	Hospital Universitari Germans Trias i Pujol ICO	Badalona	Barcelona
Spain	Hospital Universitari Vall d' Hebron	Barcelona
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Clínico San Carlos	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	MD Anderson Cancer Center Madrid	Madrid
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda	Madrid
Spain	Hospital Regional Universitario de Malaga	Malaga
Spain	Corporació Sanitaria Parc Taulí-Hospital de Sabadell	Sabadell	Barcelona
Spain	Complejo hospitalario regional virgen rocío	Sevilla
Spain	Hospital General Universitario de Valencia	Valencia
Spain	Hospital Universitario La Fe de Valencia	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Wirral
United Kingdom	Bristol Cancer Institute, UHB NHS Foundation Trust	Bristol
United Kingdom	Sarah Cannon Research Institute UK	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	The Christie NHS Fundation Trust	Manchester	Greater Manchester
United Kingdom	Worcestershire Acute Hospitals NHS Trust	Worcester
United States	Anne Arundel Medical Center Oncology and Hematology	Annapolis	Maryland
United States	Alabama Oncology	Birmingham	Alabama
United States	Boca Raton Regional Hospital Lynn Cancer Institute	Boca Raton	Florida
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Gabrail Cancer Center Research	Canton	Ohio
United States	Ironwood Physicians P.C. dba Ironwood Cancer & Research Centers	Chandler	Arizona
United States	Summit Medical Group, P.A.	Florham Park	New Jersey
United States	Holy Cross Hospital - Michael and Dianne Bienes Comprehensive Cancer Center	Fort Lauderdale	Florida
United States	The Center for Cancer and Blood Disorders	Fort Worth	Texas
United States	St Jude Hospital Yorba Linda dba St Joseph Heritage Healthcare	Fullerton	California
United States	Joliet Oncology-Hematology Associates, Ltd.	Joliet	Illinois
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Dartmouth-Hitchcock Medical Center/Mary Hitchcock Memorial Hospital	Lebanon	New Hampshire
United States	Loma Linda University Medica! Center	Loma Linda	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	East Jefferson Hematology-Oncology Metairie Physicians Services, Inc	Metairie	Louisiana
United States	Froedtert Hospital & the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Montgomery Cancer Center	Mount Sterling	Kentucky
United States	FirstHealth Outpatient Cancer Center	Pinehurst	North Carolina
United States	QUEST Research Institute	Royal Oak	Michigan
United States	Medical Oncology Associates PS (dba Summit Cancer Centers)	Spokane	Washington
United States	MultiCare Institute for Research & Innovation	Tacoma	Washington
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida
United States	Healthcare Research Network III, LLC	Tinley Park	Illinois
United States	Oklahoma Cancer Specialists and Research Institute, LLC	Tulsa	Oklahoma
United States	Tyler Hematology-Oncology PA	Tyler	Texas
United States	Associates in Hematology and Oncology, P.C.	Upland	Pennsylvania
United States	Carle Cancer Center	Urbana	Illinois
United States	Innovative Clinical Research Institute (ICRI)	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
PharmaMar

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Greece,  Hungary,  Italy,  Lebanon,  Netherlands,  Poland,  Portugal,  Romania,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Difference in Overall Survival Between Lurbinectedin/Doxorubicin (DOX) and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 12 Months	Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).	At 12 months
Secondary	Difference in Overall Survival Between Lurbinectedin/DOX and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 18 Months	Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).	At 18 months
Secondary	Difference in Overall Survival Between Lurbinectedin/DOX and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 24 Months	Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).	At 24 months
Secondary	Progression-free Survival (PFS) by Independent Review Committee	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.	Every six weeks up to progression disease, a period of approximately 3.5 years
Secondary	Progression-free Survival Rate at 6 Months by Independent Review Committee	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.	At 6 months
Secondary	Progression-free Survival Rate at 12 Months by Independent Review Committee	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.	at 12 months
Secondary	Best Antitumor Response by Independent Review Committee	Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Response Rate by Independent Review Committee	Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Duration of Response by Independent Review Committee	Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Survival in Patients With Chemotherapy-free Interval = 90 Days	Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Progression-free Survival in Patients With Chemotherapy-free Interval =90 Days	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.	Every six weeks up to progression disease, a period of approximately 3.5 years
Secondary	Best Antitumor Response in Patients With Chemotherapy-free Interval = 90 Days	Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Response Rate in Patients With Chemotherapy-free Interval = 90 Days	Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Duration of Response in Patients With Chemotherapy-free Interval = 90 Days	Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Survival in Patients With Chemotherapy-free Interval < 90 Days	Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Progression-free Survival in Patients With Chemotherapy-free Interval <90 Days	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.	Every six weeks up to progression disease, a period of approximately 3.5 years
Secondary	Best Antitumor Response in Patients With Chemotherapy-free Interval <90 Days	Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Response Rate in Patients With Chemotherapy-free Interval <90 Days	Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Duration of Response in Patients With Chemotherapy-free Interval <90 Days	Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Survival in Patients Without Central Nervous System Involvement at Baseline	Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Progression-free Survival in Patients Without Central Nervous System Involvement at Baseline	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.	Every six weeks up to progression disease, a period of approximately 3.5 years
Secondary	Best Antitumor Response in Patients Without Central Nervous System Involvement at Baseline	Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Response Rate in Patients Without Central Nervous System Involvement at Baseline	Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Duration of Response in Patients Without Central Nervous System Involvement at Baseline	Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Survival in Patients With Central Nervous System Involvement at Baseline	Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Progression-free Survival in Patients With Central Nervous System Involvement at Baseline	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.	Every six weeks up to progression disease, a period of approximately 3.5 years
Secondary	Best Antitumor Response in Patients With Central Nervous System Involvement at Baseline	Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Overall Response Rate in Patients With Central Nervous System Involvement at Baseline	Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years
Secondary	Duration of Response in Patients With Central Nervous System Involvement at Baseline	Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.; CR, complete response: disappearance of all lesions; PD, disease progression: =10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: =10% decrease in target lesion size or =15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown	Every three months up to death or study termination, a period of approximately 3.5 years