Dinutuximab and Irinotecan Versus Irinotecan to Treat Subjects With Relapsed or Refractory Small Cell Lung Cancer

Small Cell Lung Cancer Clinical Trial

Official title:

A Two-part, Open-label, Randomized, Phase 2/3 Study of Dinutuximab and Irinotecan Versus Irinotecan for Second Line Treatment of Subjects With Relapsed or Refractory Small Cell Lung Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03098030
• Other study ID #: DIV-SCLC-301
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: June 1, 2017
• Est. completion date: March 26, 2020

Study information

• Verified date: November 2020
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a 2-part, multicenter, open-label, randomized study of dinutuximab and irinotecan versus irinotecan alone in subjects with relapsed or refractory small cell lung cancer (SCLC). Part 1 of the study involves intrasubject dose escalation to evaluate the safety and tolerability of dinutuximab in combination with irinotecan. Part 2 of the study is designed to determine whether dinutuximab plus irinotecan prolongs overall survival (OS) compared with irinotecan alone. Subjects in Part 2 will be randomized in a 2:2:1 fashion to 1 of 3 treatment groups: (A) irinotecan; (B) dinutuximab plus irinotecan; or (C) topotecan. Randomization will be stratified by duration of response to prior platinum therapy (relapse-free period <3 months or ≥3 months).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 483
• Est. completion date: March 26, 2020
• Est. primary completion date: January 27, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Have histologically or cytologically confirmed SCLC (undifferentiated small-cell carcinoma arising in or consistent with lung cancer origin).

2. Documented relapse or disease progression during or after first-line platinum-based therapy (subjects refractory to initial platinum-based therapy are eligible).

3. Have no curative therapy available.

4. Have a life expectancy of at least 12 weeks.

5. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Have adequate bone marrow and hepatic function.

7. Have calculated creatinine clearance (CrCL) =30 mL/minute or serum creatinine =1.5 times below the upper limit of normal.

8. Women of reproductive potential must not be pregnant or breastfeeding and have a negative urine or serum pregnancy test obtained within 7 days prior to the first dose of study treatment.

9. Subjects must agree to consistently use 2 forms of highly effective contraception/birth control between signing of the informed consent and 60 days after the last study drug administration.

Exclusion Criteria:

1. Candidate for re-treatment with original platinum-based regimen as second-line therapy.

2. Prior treatment with irinotecan, topotecan, or dinutuximab.

3. Have active brain metastases. Subjects with brain metastases are allowed if they completed definitive brain therapy, are asymptomatic and radiologically stable, and if they are not currently receiving corticosteroids or radiation.

4. Have mixed small cell and non-small cell histologic features.

5. Have a previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta and Tis [carcinoma in situ]) or any previous cancer curatively treated <3 years ago.

6. Have a history or current evidence of uncontrolled cardiovascular disease.

7. Have not recovered from prior surgery, significant trauma, systemic anticancer therapy, radiation therapy or investigational therapy to Grade 1 or better toxicity prior to enrollment (Part 1) or randomization (Part 2).

8. Have had organ allograft or hematopoietic transplantation.

9. Known to be human immunodeficiency virus (HIV) positive.

10. Have an active infection requiring treatment or one that is clinically serious in the Investigator's opinion.

11. Have received a live vaccine within 6 months of enrollment (Part 1) or randomization (Part 2).

12. Exposure to strong CYP3A4 and/or UGT1A1 inhibitors and strong CYP3A4 inducers within 14 days of enrollment (Part 1) or randomization (Part 2).

13. Have any clinical condition that is considered unstable or might jeopardize the safety of the subject and/or influence the subject's compliance in the study.

Related Conditions & MeSH terms

• Lung Neoplasms
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma

Intervention

Biological:
• Dinutuximab
Dinutuximab injection, for intravenous (IV) use

Drug:
• Irinotecan
Irinotecan injection, IV infusion
• Topotecan
Topotecan for injection

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Ballarat Health Services	Ballarat	Victoria
Australia	Mid North Coast Cancer Institute Coff Habour Health Campus	Coffs Harbour	New South Wales
Australia	Mater Misericordiae Limited and Mater Medical Research Institute Limited	South Brisbane	Queensland
Bulgaria	Medical Oncology Department, Specialized Hospital for Active Treatment of Oncology Sveti Mina EOOD - Blagoevgrad	Blagoevgrad
Bulgaria	Department of Medical Oncology, Complex Oncology Center - Burgas EOOD, Burgas	Burgas
Bulgaria	Medical Oncology Department, Multiprofile Hospital for Active Treatment - Dobrich AD, Dobrich	Dobrich
Bulgaria	Medical Oncology Department, Multiprofile Hospital for Active Treatment - Dr. Tota Venkova AD, Gabrovo	Gabrovo
Bulgaria	Medical Oncology Department, Multiprofile Hospital for Active Treatment - Uni Hospital OOD, Panagiurishte	Panagyurishte
Bulgaria	Clinic of Oncology, UMHAT Dr. Georgi Stranski - Pleven	Pleven
Bulgaria	Clinic of Oncology, UMHAT Pulmed	Plovdiv
Bulgaria	First Department of Medical Oncology, Gastroenterology and Pulmology, Complex Oncology Center - Plovdiv EOOD	Plovdiv
Bulgaria	Clinic for Chemotherapy, Specialized Hospital for Active Treatment in Oncology EAD, Sofia	Sofia
Bulgaria	Clinic of Oncology, UMHAT SofiaMed	Sofia
Bulgaria	First Department for Medical Oncology, Multiprofile Hospital for Active Treatement Serdika EOOD, Sofia	Sofia
Bulgaria	Medical Oncology Clinic, Multiprofile Hospital for Active Treatment (MHAT) for Female's Health - Nadezhda OOD, Sofia	Sofia
Bulgaria	Medical Oncology Department, University Multiprofile Hospital for Active Treatment Sv. Ivan Rilski EAD, Sofia	Sofia
Bulgaria	Clinic of Oncology, MHAT Sveta Marina	Varna
Canada	Cross Cancer Institute - Clinical Trials Unit	Edmonton	Alberta
Canada	Horizon Health Network - The Moncton Hosoital	Moncton	New Brunswick
Canada	McGill University Health Center	Montréal	Quebec
Canada	L'Institut Universitaire de Cardiologie et de pneumologie de Quebec	Québec	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	Windsor Regional Hospital Cancer Program	Windsor	Ontario
France	Institut de Cancérologie de l'Ouest - Centre Paul Papin	Angers	Pays De La Loire
France	CHU Brest	Brest
France	URCOT : Unité de Recherche Commune en Oncologie Thoracique Service de pneumologie de l'hôpital de la Croix-Rousse	Bron	Rhône-Alpes
France	Centre François Baclesse	Caen
France	CHI Créteil	Créteil
France	Clinique Victor Hugo	Le Mans	Pays De La Loire
France	URCOT : Unité de Recherche Commune en Oncologie Thoracique Service de pneumologie de l'hôpital de la Croix-Rousse	Lyon	Rhône-Alpes
France	Hopital Nord	Marseille	Alpes-Côte d'Azur
France	Institut Paoli-Calmettes, Service Dòncologie Médicale	Marseille
France	Institut Regional du Cancer de Montpellier	Montpellier	Occitanie
France	Service de Pneumologie aiguë et Cancérologie Thoracique Centre hospitalier Lyon-Sud	Pierre Bénite	Rhône-Alpes
France	Institut de Cancérologie de l'Ouest - Centre René Gauducheau	Saint-Herblain
France	Centre Paul Strauss	Strasbourg
France	Nouvel Hôpital Civil de Strasbourg	Strasbourg
Georgia	LTD High Technology Hospital Medcenter	Batumi
Georgia	High Technology Medical Center, University Clinic	Tbilisi
Georgia	Institute of Clinical Oncology	Tbilisi
Georgia	LTD ''Accad. F. Todua Medical Center-Research Institute of Clinical Medicine''	Tbilisi
Georgia	Multiprofile Clinic Consillium Medulla	Tbilisi
Hong Kong	Princess Margaret Hospital	Kowloon
Hong Kong	Queen Elizabeth Hospital	Kowloon
Hong Kong	Queen Mary Hospital	Pokfulam
Hungary	Korányi National Institute	Budapest
Hungary	Koranyi National Institute of Pulmonology - Horváth	Budapest
Hungary	Koranyi National Institute of TBC and Pulmonology	Budapest
Hungary	Semmelweis Egyetem AOK Pulmonologiai Klinika	Budapest
Hungary	Veszprém Megyei Tüdogyógyintézet	Farkasgyepu
Hungary	Matrai Gyogyintezet	Matrahaza
Hungary	Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Oktatókórház, Semmelweis Tagkórház, Tüdogyógyászati Osztály	Miskolc
Hungary	Hetenyi Geza Hospital	Szolnok	Jasz-Nagykun-Szolnok
Hungary	Komarom-Esztergom Megyei Onkorm. Szent Borbala Korhaza	Tatabanya
Hungary	Tudogyogyintezet Torokbalint	Torokbalint
Hungary	Zala Megyei Szent Rafael Korhaz	Zalaegerszeg
India	Healthcare Global (HCG) Towers	Bangalore
India	Sri Venkateshwara Hospitals	Bangalore	Karnataka
India	Bhagawan Mahaveer Cancer Hospital	Jaipur
India	Birla Cancer Centre, SMS Hospital	Jaipur	Rajasthan
India	Jaslok Hospital & Research Center	Mumbai	Maharashtra
India	KLES Dr Prabhakar Kore Hospital & MRC	Nehru Nagar	Karnataka
India	Deenanath Mangeshkar Hospital	Pune	Maharashtra
India	Grant Medical Foundation Ruby Hall Clinic	Pune	Maharashtra
Italy	Dipartimento di Oncologia, ARNAS Garibaldi	Catania
Italy	Istituto Europeo di Oncologia (IEO), Milano	Milan
Italy	Istituto Nazionale dei Tumori	Milan
Italy	Ospedale Santa Maria della Misericordia, Perugia	Perugia
Italy	Radiation Oncology, Campus Bio-Medico University	Rome
Italy	Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena	Siena
Italy	A.O.U. San Luigi Gonzaga, Orbassano (Torino)	Torino
Korea, Republic of	Kosin University Gospel Hospital	Busan
Korea, Republic of	Chungbuk National University Hospital	Chungcheongbuk-do
Korea, Republic of	Keimyung University Dongsan Medical Centre	Daegu
Korea, Republic of	Kyungpook National University Medical Center	Daegu
Korea, Republic of	Kyungpook University Chilgok Hospital	Daegu
Korea, Republic of	Chungnam National University Hospital	Daejeon
Korea, Republic of	CHA Bundang Medical Center	Gyeonggi-do
Korea, Republic of	Seoul National University Bundang Hospital	Gyeonggi-do
Korea, Republic of	Pusan National University Yangsan Hospital	Gyeongsangnam-do
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	Chonnam National University Hwasun Hospital	Jeonnam
Korea, Republic of	Gachon Universtiy Gil Medical Center	Namdong
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Seoul National University Boramae Medical Center	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
Korea, Republic of	Wonju Severance Christian Hospital	Wonju-Si, Gangwon-do
Lithuania	Hospital of Lithuanian University of Health Sciences (LSMU) Kauno Klinikos	Kaunas
Lithuania	National Cancer Institute	Vilnius
Lithuania	Vilnius University Hospital Santaros Klinikos	Vilnius
Malaysia	Department of Medicine, Faculty of Medicine	Kuala Lumpur
Malaysia	Hospital Kuala Lumpur	Kuala Lumpur
Malaysia	Hospital Umum Sarawak	Kuching
Malaysia	National Cancer Institute	Putrajaya
Philippines	Cebu Doctors University Hospital	Cebu City
Philippines	Davao Doctors Hospital	Davao City
Philippines	Manila Doctors Hospital	Manila
Philippines	St. Luke's Medical Center - Quezon City	Quezon City
Philippines	St. Luke's Medical Centre	Quezon City
Poland	Centrum Terapii Wspolczesnej J.M. Jasnorzewska sp. komandytowo-akcyjna	Lódz	Lódz Voivodeship
Poland	Samodzielny Specjalistyczny ZespólZakladów Opieki Zdrowotnej im. dr. Teodora Dunina	Mrozy
Poland	Samodzielny Publiczny Zespól Gruzlicy i Chorób Pluc w Olsztynie	Olsztyn	Warminsko-Mazurskie
Poland	Mazowieckie Centrum Leczenia Chorob Pluc i Gruzlicy	Otwock
Poland	Szpital Chorób Pluc im Sw. Józefa w Pilchowicach	Pilchowice
Poland	Wielkopolskie Centrum Pulmonologii i Torakochirurgii im. Eugenii i Janusza Zeylandów	Poznan
Poland	Szpital Specjalistyczny w Prabutach Sp. z o.o	Prabuty	Pomeranian Voivodeship
Poland	Centrum Onkologii-Instytut im. Sklodowskiej-Curie	Warszawa
Poland	Wojskowy Instytut Medyczny	Warszawa
Romania	Oncopremium Team LTD	Baia-Mare
Romania	Institute of Oncology Prof. Dr. I.Chiricuta Cluj-Napoca	Cluj-Napoca
Romania	Medisprof LTD	Cluj-Napoca
Romania	SC Oncolab LTD	Craiova
Romania	SC Oncology Center Sf. Nectarie LTD	Craiova
Romania	Emergency County Hospital Satu-Mare, Medical Oncology Clinic	Satu-Mare
Romania	Emergency Hospital ,Sf. Ioan cel Nou'	Suceava
Romania	Oncocenter Oncology Clinic LTD	Timisoara
Russian Federation	State Budgetary Healthcare Institution of Arkhangelsk Region Arkhangelsk Clinical Oncology Dispensary	Arkhangelsk
Russian Federation	State Budgetary Healthcare Institution of Sverdlovsk Region, Sverdlovsk Regional Oncology Dispensary	Ekaterinburg
Russian Federation	Region Budgetary Healthcare Institution, Kursk Regional Clinical Oncology Dispensary of Healthcare Committee of Kursk Region	Kursk
Russian Federation	Federal State Budgetary Institution, Nati?nal Medical Research Center of Oncology n.a. N.N. Blokhin of Ministry of Healthcare of the Russian Federation	Moscow
Russian Federation	State Budgetary Healthcare Institution of Arkhangelsk region "Arkhangelsk Clinical Oncology Dispensary"	Moscow
Russian Federation	State Budgetary Healthcare Institution of Moscow, Moscow City Oncology Hospital #62 of Moscow Healthcare Department	Moscow
Russian Federation	State Budgetary Healthcare Institution of Novosibirsk Region, ?ity Clinical Hospital #1	Novosibirsk
Russian Federation	State Budgetary Healthcare Institution of Novosibirsk Region, Novosibirsk Regional Oncology Dispensary	Novosibirsk
Russian Federation	Budgetary Healthcare Institution of Omsk Region, Clinical Oncology Dispensary	Omsk
Russian Federation	State Budgetary Healthcare Institution, Orenburg Regional Clinical Oncology Dispensary	Orenburg
Russian Federation	Center of Palliative Care-Devita LLC	Saint Petersburg
Russian Federation	BioEq, LLC	Saint-Petersburg
Russian Federation	Federal State Budgetary Institution, Scientific Research Institute of Oncology n.a. Petrov	Saint-Petersburg
Russian Federation	Saint-Petersburg State Budgetary Healthcare Institution, City Clinical Oncology Dispensary	Saint-Petersburg
Russian Federation	State Budgetary Healthcare Institution, Leningrad Regional Clinical Hospital	Saint-Petersburg
Russian Federation	State Budgetary Healthcare Institution, Saint-Petersburg Clinical Scientific Practical Center of Specialized Kinds of Medical Care (Oncological)	Saint-Petersburg
Russian Federation	State Budgetary Healthcare Institution, Samara Regional Clinical Oncology Dispensary	Samara
Russian Federation	State Budgetary Healthcare Institution of Yaroslavl Region, Regional Oncology Hospital	Yaroslavl
Slovakia	Faculty Hospital Zilina	Žilina
Slovakia	St. Jacob´s Hospital Bardejov - Department of Clinical Oncology	Bardejov
Spain	Hospital General de Alicante	Alicante
Spain	Hospital Quirón Dexeus	Barcelona
Spain	Hospital Universitari Vall d´Hebron	Barcelona
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	CHU A Coruña	Coruña	Galicia
Spain	Hospital General Universitario de Elche	Elche	Alicante
Spain	Instituto Catalán de Oncología (ICO) - Josep Trueta	Girona
Spain	Hospital Universitario Lucus Augusti	Lugo
Spain	H. M. Puerta del Sur (H. Móstoles)	Madrid
Spain	Hospital General Universitário Gregorio Marañón	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Madrid Norte Sanchinarro	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda	Madrid
Spain	Hospital Regional de Málaga (H. Carlos Haya)	Málaga
Spain	Complexo Hospitalario Universitario de Ourense (CHUO)	Ourense
Spain	Complejo Hospitalario de Navarra	Pamplona	Navarra
Spain	Hospital Virgen de los Lirios Alcoy	Planta
Spain	Corporació Sanitària Parc Taulí	Sabadell
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen de Valme	Sevilla
Spain	Hospital Universitario y Politécnico de La Fe	Valencia
Spain	Hospital Álvaro Cunqueiro	Vigo
Spain	Hospital Lozano Blesa	Zaragoza
Taiwan	E-Da Hospital	Kaohsiung City
Taiwan	E-Da Hospital	Kaohsiung City
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung City
Taiwan	Chung Shan Medical University Hospital	Taichung City
Taiwan	Chi Mei Hospital, Liouying	Tainan City
Taiwan	Chang-Gung Memorial Hospital, Linkou	Taoyuan City
Thailand	King Chulalongkorn Memorial Hospital	Bangkok
Thailand	National Cancer Institute of Thailand	Bangkok
Thailand	Siriraj Hopsital	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai
Thailand	Srinagarind Hospital	Khon Kaen
Thailand	Naresuan University Hospital	Phitsanulok
Thailand	Songklanagarind Hospital	Songkhla
Ukraine	Regional Communal Nonprofit Enterprise, Municipal Institution Chernivtsi Regional Clinical Oncology Dispensary, Surgery Department, State Higher Educational Establishment of Ukraine, Bukovinian State Medical University, Department of Onc and Radiology	Chernivtsi
Ukraine	Municipal Non-profit Enterprise "City Clinical Hospital #4" of Dnipro City Council," Municipal Institution "Multifield Dnipropetrovsk City Hospital #4" of Dnipropetrovsk Regional Council, Department of Chemotherapy	Dnipro	Dnipropetrovsk
Ukraine	Communal Non-profit Enterprise "Kyiv City Clinical Oncology Center" of Executive body of Kyiv City Council, Kyiv City Clinical Oncology Center by Main Department of Health Protection Kyiv, Hospital of Day Stay for Oncology Patients	Kiev
Ukraine	Municipal Nonprofit Institution "Odessa Regional Oncology Dispensary" of Odessa Regional Council, Municipal Institution Odesa Regional Oncology Dispensary, Hospital of Day Stay (Unit of Dispensary-Polyclinic Department)	Odessa
Ukraine	Municipal Nonprofit Institution "Cental Municipal Clinical Hospital" of Uzhgorod City Council, Municipal Oncology Centre	Uzhgorod	Zakarpattia
Ukraine	Municipal Nonprofit Institution "Podilsky Regional Oncology Center" of Vinnytsa City Council, Podilsky Regional Oncology ?enter, Department of Chemotherapy	Vinnitsya
United Kingdom	Royal Marsden Hospital	Chelsea	London
United Kingdom	Princess Alexandra Hospital	Harlow	Essex
United Kingdom	St James' Institute of Oncology	Leeds
United Kingdom	Guy's and St Thomas' NHS Foundation Trust	London
United Kingdom	Royal Free Hospital	London
United Kingdom	St Bartholomew's Hospital	London
United Kingdom	Royal Marsden Hospital	Sutton
United States	The University of New Mexico Comprehensive Cancer Center	Albuquerque	New Mexico
United States	Alaska Clinical Research Center	Anchorage	Alaska
United States	Texas Health Physicians Group	Arlington	Texas
United States	Winship Cancer Institute, Emory University	Atlanta	Georgia
United States	Billings Clinic Cancer Center	Billings	Montana
United States	St. Vincent Frontier Cancer Center	Billings	Montana
United States	United Hospital Center	Bridgeport	West Virginia
United States	Physicians' Clinic of Iowa Hematology and Oncology	Cedar Rapids	Iowa
United States	Charleston Oncology	Charleston	South Carolina
United States	UH Cleveland Medical Center	Cleveland	Ohio
United States	Alpha Oncology Research LLC	DeBary	Florida
United States	Cancer Treatment Centers of America - Western Regional Medical Center	Goodyear	Arizona
United States	Hartford Hospital	Hartford	Connecticut
United States	Kentucky Cancer Clinic	Hazard	Kentucky
United States	Genesis Cancer Center	Hot Springs	Arkansas
United States	21st Century Oncology	Jacksonville	Florida
United States	Center for Biomedical Research	Knoxville	Tennessee
United States	University of Kentucky	Lexington	Kentucky
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	21st Century Oncology	Louisville	Kentucky
United States	University of Wisoncsin - Carbone Cancer Ctr	Madison	Wisconsin
United States	Northwest Georgia Oncology Centers, P.C.	Marietta	Georgia
United States	Baptist Health Floyd Cancer Center	New Albany	Indiana
United States	Eastern Connecticut Hematology and Oncology Assoc	Norwich	Connecticut
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	Camden Clark Medical Center / Regional Cancer Center	Parkersburg	West Virginia
United States	Cancer Treatment Centers of America at Eastern Regional Medical Center	Philadelphia	Pennsylvania
United States	Fox Chase Cancer Center Office of Clinical Research	Philadelphia	Pennsylvania
United States	Plano Cancer Institute	Plano	Texas
United States	Kaiser Permanente Northwest Center for Health Research CRSS	Portland	Oregon
United States	Comprehensive Hematology Oncology	Saint Petersburg	Florida
United States	Vista Oncology (Shelton office)	Shelton	Washington
United States	Spartanburg Medical Center/Gibbs Cancer Center and Research Institute	Spartanburg	South Carolina
United States	Cox Health Medical	Springfield	Missouri
United States	Olive View - UCLA	Sylmar	California
United States	Innovative Clinical Research Institute	Tucson	Arizona
United States	Cancer Treatment Centers of America at Southwestern RMC	Tulsa	Oklahoma
United States	The University of Texas Health Science Center at Tyler, Office of Clinical Studies	Tyler	Texas
United States	Prairie Lakes Health Care	Watertown	South Dakota
United States	Innovative Clinical Research Institute	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
United Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Bulgaria,  Canada,  France,  Georgia,  Hong Kong,  Hungary,  India,  Italy,  Korea, Republic of,  Lithuania,  Malaysia,  Philippines,  Poland,  Romania,  Russian Federation,  Slovakia,  Spain,  Taiwan,  Thailand,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	OS will be derived as: (date of death - date of randomization) + 1. Subjects who are alive or permanently lost to follow-up at the cut-off date for the analysis will be censored at the last date the subject was known to be alive.	Up to approximately 2.5 years
Secondary	Progression-free Survival (PFS)	PFS will be defined as the time from the date of randomization to the date of first documentation of tumor progression or death from any cause, whichever occurs first.	Up to approximately 2.5 years
Secondary	Objective Response Rate (ORR)	The ORR is the percentage of subjects with best overall response of either complete response (CR) or partial response (PR); ORR = CR + PR. Per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, CR was defined as the disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters as confirmed by CT or MRI.	Up to approximately 2.5 years
Secondary	Clinical Benefit Rate (CBR)	The CBR is defined as the percentage of subjects with either a CR, PR, or stable disease (SD), relative to the number of subjects in the treatment group. Per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, CR was defined as the disappearance of all target lesions; PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study, as confirmed by CT or MRI .	Up to approximately 2.5 years