Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer

Urothelial Cancer Clinical Trial

— EV-302  

Official title:

An Open-label, Randomized, Controlled Phase 3 Study of Enfortumab Vedotin in Combination With Pembrolizumab Versus Chemotherapy Alone in Previously Untreated Locally Advanced or Metastatic Urothelial Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04223856
• Other study ID #: SGN22E-003
• Secondary ID: 2019-004542-15MK
• Status: Recruiting
• Phase: Phase 3
• Start date: March 30, 2020
• Est. completion date: September 30, 2027

Study information

• Verified date: May 2024
• Source: Astellas Pharma Inc
• Contact: Seagen Inc. Trial Information Support
• Phone: 866-333-7436
• Email: clinicaltrials[@]seagen.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is being done to see how well two drugs (enfortumab vedotin and pembrolizumab) work together to treat patients with urothelial cancer. The study will compare these drugs to other drugs that are usually used to treat this cancer (standard of care). The patients in this study will have cancer that has spread from their urinary system to other parts of their body.

Description:

Japan PMDA has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan.

This study is being conducted to evaluate the combination of enfortumab vedotin + pembrolizumab versus standard of care gemcitabine + platinum-containing chemotherapy, in subjects with previously untreated locally advanced or metastatic urothelial cancer.

Enfortumab vedotin may be administered for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs. Pembrolizumab may be administered for a maximum of 35 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first. Cisplatin or carboplatin plus gemcitabine may be administered for a maximum of 6 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 990
• Est. completion date: September 30, 2027
• Est. primary completion date: August 8, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically documented, unresectable locally advanced or metastatic urothelial carcinoma

• Measurable disease by investigator assessment according to RECIST v1.1

• Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy

• Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:

• Participants that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted

• Participants that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted

• Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment

• Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization

• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2

• Adequate hematologic and organ function

Exclusion Criteria:

• Previously received enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADCs)

• Received prior treatment with a programmed cell death ligand-1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage urothelial cancer (UC), defined as a PD-1 inhibitor or PD-L1 inhibitor

• Received prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor

• Received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment

• Uncontrolled diabetes

• Estimated life expectancy of less than 12 weeks

• Active central nervous system (CNS) metastases

• Ongoing clinically significant toxicity associated with prior treatment that has not resolved to = Grade 1 or returned to baseline

• Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.

• Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection.

• History of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy

• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months prior to randomization

• Receipt of radiotherapy within 2 weeks prior to randomization

• Received major surgery (defined as requiring general anesthesia and >24 hour inpatient hospitalization) within 4 weeks prior to randomization

• Known severe (= Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin

• Active keratitis or corneal ulcerations

• History of autoimmune disease that has required systemic treatment in the past 2 years

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan

• Prior allogeneic stem cell or solid organ transplant

• Received a live attenuated vaccine within 30 days prior to randomization

Related Conditions & MeSH terms

• Urothelial Cancer

Intervention

Drug:
• Enfortumab vedotin
Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle
• Pembrolizumab
IV infusion on Day 1 of every 3-week cycle
• Cisplatin
administered as IV infusion on Day 1 of each 3-week cycle
• Carboplatin
Dosed according to local guidelines and will be administered as IV infusion on Day 1 of each 3-week cycle
• Gemcitabine
IV infusion on Days 1 and 8 of every 3 week cycle

Locations

Country	Name	City	State
Argentina	Site AR54008	Buenos Aire
Argentina	Site AR54011	Caba
Argentina	Site AR54005	Cordoba
Argentina	Site AR54006	La Rioja
Argentina	Site AR54004	Mendoza
Argentina	Site AR54001	Rosario
Argentina	Site AR54002	San Miguel
Argentina	Site AR54012	Tucuman
Argentina	Site AR54003	Viedma
Australia	Site AU61003	Box Hill
Australia	Site AUS61001	Douglas
Australia	Site AUS61004	Heidelberg
Australia	Site AUS61002	Macquarie Park
Australia	Site AUS61006	South Australia
Australia	Site AU61005	South Brisbane
Belgium	Site BE32003	Brussels
Belgium	Site BE32002	Ghent
Belgium	Site BE32001	Liege
Belgium	Site BE32007	Lueven
Belgium	Site BE32006	Roeselare
Canada	Site CA11004	Calgary	Alberta
Canada	Site CA11003	Edmonton	Alberta
Canada	Site CA11002	Hamilton	Ontario
Canada	Site CA11009	London	Ontario
Canada	Site CA11001	Montreal	Quebec
Canada	Site CA11010	Montreal	Quebec
Canada	Site CA11011	Oshawa	Ontario
Canada	Site CA11008	Quebec
Canada	Site CA11005	Toronto	Ontario
Canada	Site CA11012	Toronto	Ontario
Canada	Site CA11006	Vancouver	British Columbia
China	Site CN86001	Beijing
China	Site CN86004	Beijing
China	Site CN86005	Beijing
China	Site CN86009	Beijing City
China	Site CN86015	Bengbu
China	Site CN86003	Changchun
China	Site CN86006	Changsha
China	Site CN86016	Changsha
China	Site CN86010	Chengdu
China	Site CN86007	Chongqing
China	Site CN86024	Chongqing
China	Site CN86028	Fuzhou
China	Site CN86002	Guangzhou
China	Site CN86020	Gunagzhou
China	Site CN86013	Hangzhou
China	Site CN86018	Hangzhou
China	Site CN86022	Hangzhou
China	Site CN86025	Hefei
China	Site CN86027	Jinan
China	Site CN86012	Nanjing
China	Site CN86017	Nanjing
China	Site CN86021	Ningbo
China	Site CN86014	Shanghai
China	Site CN86011	Shenyang City
China	Site CN86019	Tianjin
China	Site CN86023	Tianjin
China	Site CN86029	Wenzhou
China	Site CN86008	Wuhan City
China	Site CN86030	Xicheng District
China	Site CN86026	Xuzhou
Czechia	Site CZ42006	Brno
Czechia	Site CZ42001	Hradec Kralove
Czechia	Site CZ42004	Olomouc
Czechia	Site CZ42005	Praha 4-Krc
Denmark	Site DK45001	Aalborg
Denmark	Site DK45003	Aarhus N
France	Site FR33014	Bordeaux
France	Site FR33016	Lyon
France	Site FR33003	Nice Cedex 2
France	Site FR33020	Pierre-Bénite
France	Site FR33013	Strasbourg
France	Site FR33017	TOURS Cedex 09
France	Site FR33011	Villejuif-Cedex-France
Germany	Site DE49003	Berlin
Germany	Site DE49013	Bielefeld
Germany	Site DE49016	Düsseldorf
Germany	Site DE49014	Erlangen
Germany	Site DE49011	Essen
Germany	Site DE49007	Frankfurt am Main
Germany	Site DE49015	Gottingen
Germany	Site DE49005	Heidelberg
Germany	Site DE49009	Herne
Germany	Site DE49006	Jena
Germany	Site DE49001	Lubeck
Germany	Site DE49008	Magdeburg
Germany	Site DE49012	Mannheim
Germany	Site DE49002	Munchen
Germany	Site DE49004	Tübingen
Germany	Site DE49010	Ulm
Hungary	Site HU36002	Budapest
Hungary	Site HU36003	Budapest
Hungary	Site HU36006	Debrecen
Hungary	Site HU36001	Nyiregyhaza
Hungary	Site HU36005	Szolnok
Israel	Site IL97203	Beer Sheva
Israel	Site IL97201	Haifa
Israel	Site IL97209	Holon
Israel	Site IL97206	Jerusalem
Israel	Site IL97202	Kfar Saba
Israel	Site IL97208	Petach Tikva
Israel	Site IL97211	Rehovot
Israel	Site IL97210	Tel Aviv
Israel	Site IL97204	Tel Hashomer
Israel	Site IL97205	Zerifin
Italy	Site IT39005	Areezo
Italy	Site IT39008	Candiolo
Italy	Site IT39009	Cremona
Italy	Site IT39006	Genova
Italy	Site IT39003	Meldola
Italy	Site IT39007	Milano
Italy	Site IT39014	Milano
Italy	Site IT39004	Pisa
Italy	Site IT39002	Terni
Italy	Site IT39011	Torrette
Italy	Site IT39001	Verona
Japan	Site JP81002	Bunkyo City
Japan	Site JP81009	Chiba
Japan	Site JP81018	Chiba
Japan	Site JP81013	Fukuoka
Japan	Site JP81020	Fukuoka
Japan	Site JP81011	Hirosaki
Japan	Site JP81006	Kawasaki-shi
Japan	Site JP81001	Koto-ku
Japan	Site JP81017	Kyoto
Japan	Site JP81015	Niigata
Japan	Site JP81005	Okayama
Japan	Site JP81008	Osaka
Japan	Site JP81016	Osakasayama-Shi
Japan	Site JP81007	Sapporo
Japan	Site JP81012	Sendai-city
Japan	Site JP81014	Tokushima
Japan	Site JP81019	Tokyo
Japan	Site JP81003	Toyama
Japan	Site JP81004	Tsukuba
Japan	Site JP81010	Ube
Korea, Republic of	Site KR82001	Daejeon
Korea, Republic of	Site KR82002	Goyang-si
Korea, Republic of	Site KR82008	Hwasun
Korea, Republic of	Site KR82004	Seongnam-si
Korea, Republic of	Site KR82003	Seoul
Korea, Republic of	Site KR82005	Seoul
Korea, Republic of	Site KR82006	Seoul
Korea, Republic of	Site KR82007	Seoul
Netherlands	Site NL31001	Amsterdam
Netherlands	Site NL31002	Amsterdam
Netherlands	Site NL31005	Amsterdam, Noord-Holland
Netherlands	Site NL31007	Leeuwarden
Netherlands	Site NL31004	Nieuwegein
Netherlands	Site NL31003	Rotterdam
Netherlands	Site NL31006	Utrecht
Poland	Site PL48002	Warszawa
Russian Federation	Site RU70016	Arkhangelsk
Russian Federation	Site RU70013	Barnaul
Russian Federation	Site RU70020	Ivanovo
Russian Federation	Site RU70014	Krasnoyarsk
Russian Federation	Site RU70006	Leningradskaya Oblast'
Russian Federation	Site RU70003	Moscow
Russian Federation	Site RU70004	Moscow
Russian Federation	Site RU70011	Moscow
Russian Federation	Site RU70017	Nizhniy Novgorod
Russian Federation	Site RU70002	Omsk
Russian Federation	Site RU70019	Pyatigorsk
Russian Federation	Site RU70007	Saint Petersburg
Russian Federation	Site RU70010	Saint Petersburg
Russian Federation	Site RU70012	Saint-Petersburg
Russian Federation	Site RU70009	Saransk
Russian Federation	Site RU70008	St. Petersburg
Russian Federation	Site RU70015	Tyumen
Russian Federation	Site RU70005	Ufa
Singapore	Site SG65001	Singapore
Singapore	Site SG65002	Singapore
Singapore	Site SG65003	Singapore
Spain	Site ES34001	Barcelona
Spain	Site ES34006	Barcelona
Spain	Site ES34008	Barcelona
Spain	Site ES34010	Barcelona
Spain	Site ES34017	Barcelona
Spain	Site ES34013	Cordoba
Spain	Site ES34021	Lugo
Spain	Site ES34002	Madrid
Spain	Site ES34003	Madrid
Spain	Site ES34015	Madrid
Spain	Site ES34018	Madrid
Spain	Site ES34004	Manresa
Spain	Site ES34020	Pamplona
Spain	Site ES34016	Sabadell
Spain	Site ES34012	Santander
Spain	Site ES34007	Sevilla
Spain	Site ES34009	Valencia
Spain	Site ES34019	Valencia
Switzerland	Site CH41004	Basel
Switzerland	Site CH41002	Bern
Switzerland	Site CH41001	Chur
Switzerland	Site CH41003	Winterthur
Taiwan	Site TW88603	Kaohsiung
Taiwan	Site TW88602	Kweishan
Taiwan	Site TW88606	Taichung
Taiwan	Site TW88607	Taichung
Taiwan	Site TW88604	Tainan
Taiwan	Site TW88601	Taipei
Taiwan	Site TW88605	Taipei
Thailand	Site TH66003	Bangkok
Thailand	Site TH66004	Bangkok
Thailand	Site TH66005	Chiang Mai
Thailand	Site TH66002	HatYai
Thailand	Site TH66006	Krung Thep Maha Nakhon
Thailand	Site TH66007	Muang
Thailand	Site TH66001	Ratchathewi
Turkey	Site TR90007	Ankara
Turkey	Site TR90009	Ankara
Turkey	Site TR90005	Antalya
Turkey	Site TR90004	Edirne
Turkey	Site TR90002	Istanbul
Turkey	Site TR90003	Istanbul
Turkey	Site TR90008	Istanbul
Turkey	Site TR90001	Konya
Turkey	Site TR90006	Malatya
United Kingdom	Site UK44005	Glasgow
United Kingdom	Site UK44001	London
United Kingdom	Site UK44009	London
United Kingdom	Site UK44006	Oxford
United Kingdom	Site UK44010	Plymouth
United Kingdom	Site UK44002	Preston
United Kingdom	Site UK44003	Sheffield
United Kingdom	Site UK44008	Southampton
United States	New Mexico Cancer Center	Albuquerque	New Mexico
United States	Winship Cancer Institute / Emory University School of Medicine	Atlanta	Georgia
United States	Rocky Mountain Cancer Centers - Aurora	Aurora	Colorado
United States	University of Colorado Hospital / University of Colorado	Aurora	Colorado
United States	Johns Hopkins Medical Center	Baltimore	Maryland
United States	Maine Health Cancer Care	Biddeford	Maine
United States	Providence St Joseph Medical Center	Burbank	California
United States	Ironwood Cancer & Research Centers - Chandler	Chandler	Arizona
United States	University of Virginia	Charlottesville	Virginia
United States	The Cleveland Clinic	Cleveland	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Cancer Centers of Colorado - Denver	Denver	Colorado
United States	City of Hope National Medical Center	Duarte	California
United States	West Cancer Center & Research Institute	Germantown	Tennessee
United States	Saint Francis Hospital / Bon Secours - South Carolina	Greenville	South Carolina
United States	Vidant Medical Center	Greenville	North Carolina
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	University of California Los Angeles Medical Center	Los Angeles	California
United States	Georgia Cancer Specialists / Northside Hospital Cancer Institute	Marietta	Georgia
United States	Louisiana State University/ East Jefferson General Hospital	Metairie	Louisiana
United States	Yale Cancer Center	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	New York University (NYU) Cancer Institute	New York	New York
United States	Eastern CT Hematology and Oncology Associates	Norwich	Connecticut
United States	University of California Irvine - Newport	Orange	California
United States	Hillman Cancer Center / University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Seattle Cancer Care Alliance / University of Washington	Seattle	Washington
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	Toledo Clinic Cancer Center	Toledo	Ohio
United States	Arizona Oncology Associates PD - HOPE	Tucson	Arizona
United States	UT Health East Texas Hope Cancer Center	Tyler	Texas
United States	Lombardi Cancer Center / Georgetown University Medical Center	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.	Merck Sharp & Dohme LLC, Seagen Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  China,  Czechia,  Denmark,  France,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Russian Federation,  Singapore,  Spain,  Switzerland,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration of progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR) (Arms A and B only, global population)	Defined as the time from randomization to first documentation of disease progression per RECIST v1.1 by BICR, or to death due to any cause, whichever comes first.	Up to approximately 5 years
Primary	Duration of Overall survival (OS) (Arms A and B only, global population)	OS is defined as the time from date of randomization to date of death due to any cause.	Up to approximately 5 years
Secondary	Objective response rate (ORR) per RECIST v1.1 by BICR (Arms A and B only)	Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1	Up to approximately 5 years
Secondary	Time to pain progression (TTPP) (Arms A and B only)	Defined as the time from randomization to the first date a subject experiences a pain progression. Pain progression is defined as either an increase of 2 or more points from baseline on question 3 of the Brief Pain Inventory - Short Form (BPI-SF) or initiation of new opioid pain medication.	Up to approximately 5 years
Secondary	Mean change from baseline in worst pain at Week 26 (Arms A and B only)	Using the BPI-SF question 3, mean change from baseline in worst pain will be calculated for each postbaseline assessment timepoint for Arm A and Arm B.	Up to approximately 6 months
Secondary	Duration of PFS per RECIST v1.1 by investigator assessment (Arms A and B only)	Defined as the time from randomization to first documentation of disease progression per RECIST v1.1, or to death due to any cause, whichever comes first	Up to approximately 5 years
Secondary	ORR per RECIST v1.1 by investigator assessment (Arms A and B only)	Defined as the proportion of subjects with confirmed CR or PR according to RECIST v1.1	Up to approximately 5 years
Secondary	Duration of response (DOR) per RECIST v1.1 by BICR (Arms A and B only)	Defined as the time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause, whichever comes first	Up to approximately 5 years
Secondary	DOR per RECIST v1.1 by investigator assessment (Arms A and B only)	Defined as the time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause, whichever comes first	Up to approximately 5 years
Secondary	Disease control rate (DCR) per RECIST v1.1 by BICR (Arms A and B only)	Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1	Up to approximately 5 years
Secondary	DCR per RECIST v1.1 by investigator assessment (Arms A and B only)	Defined as the proportion of subjects with confirmed CR, PR, or SD according to RECIST v1.1	Up to approximately 5 years
Secondary	Change from baseline in patient reported outcome assessment measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L)	The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a generic, preference-based measure of health outcomes. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems). A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions. This questionnaire also records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale.	Up to approximately 5 years
Secondary	Mean scores in patient reported outcome assessment measured by the EQ-5D-5L	The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a generic, preference-based measure of health outcomes. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems). A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions. This questionnaire also records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale.	Up to approximately 5 years
Secondary	Change from baseline in patient reported outcome assessment measured by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)	EORTC-QLQ-C30 is a cancer-specific 30-item questionnaire. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.	Up to approximately 5 years
Secondary	Mean scores in patient reported outcome assessment measured by EORTC QLQ-C30	EORTC-QLQ-C30 is a cancer-specific 30-item questionnaire. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.	Up to approximately 5 years
Secondary	Incidence of adverse events (AEs)	Descriptive statistics will be used to summarize results	Up to approximately 5 years
Secondary	Incidence of laboratory abnormalities	Descriptive statistics will be used to summarize results	Up to approximately 5 years
Secondary	Treatment discontinuation rate due to AEs	Descriptive statistics will be used to summarize results	Up to approximately 5 years