A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)
NCT ID: NCT03474107
Last Updated: 2026-01-09
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
608 participants
INTERVENTIONAL
2018-06-27
2025-11-27
Brief Summary
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This study compared progression-free survival on study therapy (PFS1); the overall response rate (ORR) and the disease control rate (DCR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 of participants treated with EV to participants treated with chemotherapy.
In addition, this study evaluated the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy and assessed the safety and tolerability of EV, as well as, the quality of life (QOL) and Patient Reported Outcomes (PRO) parameters.
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Detailed Description
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Participants considered an adult according to local regulation at the time of obtaining informed consent participated in the study.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Arm A: Enfortumab Vedotin 1.25 mg/kg
Participants received 1.25 milligrams per kilogram (mg/kg) of body weight enfortumab vedotin by intravenous infusion over approximately 30 minutes on days 1, 8 and 15 of every 28-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.
Enfortumab Vedotin
Intravenous infusion
Arm B: Chemotherapy
Participants received either 75 milligrams per square meter (mg/m\^2) docetaxel by IV infusion over approximately 1 hour or 320 mg/m\^2 vinflunine by IV infusion over approximately 20 minutes or 175 mg/m\^2 paclitaxel by IV infusion over approximately 1 hour on day 1 of every 21-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.
Docetaxel
Intravenous infusion
Vinflunine
Intravenous infusion
Paclitaxel
Intravenous infusion
Cross-over Extension (COE)
Eligible participants from chemotherapy arm who met the criteria for COE will receive 1.25 mg/kg of body weight enfortumab vedotin by intravenous infusion over approximately 30 minutes on days 1, 8 and 15 of every 28-day cycle until discontinuation criteria is met.
Enfortumab Vedotin
Intravenous infusion
Interventions
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Enfortumab Vedotin
Intravenous infusion
Docetaxel
Intravenous infusion
Vinflunine
Intravenous infusion
Paclitaxel
Intravenous infusion
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Subject has histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible.
* Subject must have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease. Subjects who discontinued CPI treatment due to toxicity are eligible provided that the subjects have evidence of disease progression following discontinuation. The CPI need not be the most recent therapy. Subjects for whom the most recent therapy has been a non-CPI based regimen are eligible if the subjects have progressed/relapsed during or after the subjects most recent therapy. Locally advanced disease must not be amenable to resection with curative intent per the treating physician.
* Subject must have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting. If platinum was administered in the adjuvant/neoadjuvant setting subject must have progressed within 12 months of completion.
* Subject has radiologically documented metastatic or locally advanced disease at baseline.
* An archival tumor tissue sample should be available for submission to central laboratory prior to study treatment. If an archival tumor tissue sample is not available, a fresh tissue sample should be provided. If a fresh tissue sample cannot be provided due to safety concerns, enrollment into the study must be discussed with the medical monitor.
* Subject has ECOG PS of 0 or 1
* The subject has the following baseline laboratory data:
* absolute neutrophil count (ANC) ≥ 1500/mm3
* platelet count ≥ 100 × 10\^9/L
* hemoglobin ≥ 9 g/dL
* serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease
* creatinine clearance (CrCl) ≥ 30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection (glomerular filtration rate \[GFR\] can also be used instead of CrCl)
* alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 3 x ULN for subjects with liver metastases
* Female subject must either:
* Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy).
* Or, if of childbearing potential: Agree not to try to become pregnant during the study and for at least 6 months after the final study drug administration, and have a negative urine or serum pregnancy test within 7 days prior to Day 1 (Females with false positive results and documented verification of negative pregnancy status are eligible for participation), and if heterosexually active, agree to consistently use a condom plus 1 form of highly effective birth control per locally accepted standards starting at screening and throughout the study period and for at least 6 months after the final study drug administration.
* Female subject must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
* A sexually active male subject with female partner(s) who is of childbearing potential is eligible if:
* Agrees to use a male condom starting at screening and continue throughout the study treatment and for at least 6 months after final study drug administration. If the male subject has not had a vasectomy or is not sterile as defined below the subjects female partner(s) is utilizing 1 form of highly effective birth control per locally accepted standards starting at screening and continue throughout study treatment and for at least 6 months after the male subject receives final study drug administration.
* Male subject must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final study drug administration.
* Male subject with a pregnant or breastfeeding partner(s) must agree to abstinence or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final study drug administration.
* Subject agrees not to participate in another interventional study while on treatment in present study.
* Institutional review board (IRB)/ independent ethics committee (IEC) approved written COE informed consent and privacy language as per national regulations (e.g., health insurance portability and accountability act \[HIPAA\] Authorization for US sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
* Subject was randomized to Arm B and is either currently on study treatment or has discontinued study treatment due to intolerance, AE or progression of disease and has not started a new systemic anticancer treatment.
Exclusion Criteria
* Subject has active central nervous system (CNS) metastases. Subjects with treated CNS metastases are permitted on study if all the following are true:
* CNS metastases have been clinically stable for at least 6 weeks prior to screening
* If requiring steroid treatment for CNS metastases, the subject is on a stable dose ≤ 20 mg/day of prednisone or equivalent for at least 2 weeks
* Baseline scans show no evidence of new or enlarged brain metastasis
* Subject does not have leptomeningeal disease
* Subject has ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery). Subject with ≤ Grade 2 immunotherapy-related hypothyroidism or panhypopituitarism may be enrolled when well-maintained/controlled on a stable dose of hormone replacement therapy (if indicated). Subjects with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Subjects with ongoing immunotherapy related colitis, uveitis, or pneumonitis or subjects with other immunotherapy related AEs requiring high doses of steroids (\> 20 mg/day of prednisone or equivalent) are excluded.
* Subject has prior treatment with EV or other monomethyl auristatin E (MMAE)-based Antibody drug conjugates (ADCs).
* Subject has received prior chemotherapy for urothelial cancer with all available study therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy).
* Subject has received more than 1 prior chemotherapy regimen for locally advanced or metastatic urothelial cancer, including chemotherapy for adjuvant or neo-adjuvant disease if recurrence occurred within 12 months of completing therapy. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen.
* Subject has history of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
* Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or fungal infection at the time of first dose of EV. Routine antimicrobial prophylaxis is permitted.
* Subject has known active Hepatitis B (e.g., hepatitis B surface antigen (HBsAg) reactive) or active hepatitis C (e.g., hepatitis C virus (HCV) Ribonucleic Acid (RNA) \[qualitative\] is detected).
* Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2).
* Subject has documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of study drug.
* Subject has radiotherapy or major surgery within 4 weeks prior to first dose of study drug.
* Subject has had chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug.
* Subject has known hypersensitivity to EV or to any excipient contained in the drug formulation of EV; OR subject has known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells.
* Subject has known hypersensitivity to the following: docetaxel or to any of the other excipients listed in product label, including polysorbate 80, paclitaxel or to any of the other excipients listed in product label, such as macrogolglycerol ricinoleate 35 (Ph.Eur.); and vinflunine or to any of the other excipients listed in product label such as other vinca alkaloids (vinblastine,vincristine, vindesine, vinorelbine).
* Subject has known active keratitis or corneal ulcerations.
* Subject has other underlying medical condition that would impair the ability of the subject to receive or tolerate the planned treatment and follow-up.
* History of uncontrolled diabetes mellitus within 3 months of the first dose of study drug. Uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥ 8% or HbA1c between 7 and \< 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
* Subject has been diagnosed with a new malignancy while on Arm B in the EV-301 study. Subjects with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
* Subject has already started commercial EV or arrangements have been made for subject to start commercial EV which is reimbursed in their country. Additionally, if EV is commercially available with reimbursement in the potential subject's country, the subject can consider transitioning to the commercial product unless otherwise discussed with sponsor.
18 Years
ALL
No
Sponsors
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Seagen Inc.
INDUSTRY
Astellas Pharma Global Development, Inc.
INDUSTRY
Responsible Party
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Principal Investigators
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Medical Director
Role: STUDY_DIRECTOR
Astellas Pharma Global Development, Inc.
Locations
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UCI Chao Family Comprehensive Cancer Center
Orange, California, United States
University of California
Sacramento, California, United States
Innovative Clinical Research
Whittier, California, United States
University of Colorado
Denver, Colorado, United States
Smilow Cancer Hospital at Yale-New Haven
New Haven, Connecticut, United States
Sylvester Comprehensive Cancer Center
Miami, Florida, United States
Florida Hospital
Orlando, Florida, United States
Rush University Medical Center
Chicago, Illinois, United States
Norton Cancer Institute
Louisville, Kentucky, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Nebraska Cancer Specialists
Omaha, Nebraska, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Long Island Jewish Medical Center
Lake Success, New York, United States
Sidney Kimmel Center for Prostate and Urologic Cancers
New York, New York, United States
Montefiore Medical Center
The Bronx, New York, United States
White Plains Hospital Center for Cancer Care - Oncology Site
White Plains, New York, United States
Toledo Clinic Cancer Center
Toledo, Ohio, United States
Providence Portland Med Center
Portland, Oregon, United States
University of Pennsylvania
Philadelphia, Pennsylvania, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Lifespan Rhode Island Hospital
Providence, Rhode Island, United States
Saint Francis Hospital
Greenville, South Carolina, United States
HOPE Cancer Center of East Texas
Tyler, Texas, United States
Benaroya Research Institute at Virginia Mason
Seattle, Washington, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Site AR54001
Buenos Aires, , Argentina
Site AU61006
Adelaide, , Australia
Site AU61001
Miranda, , Australia
Site AU61004
St Leonards, , Australia
Site AU61002
Sydney, , Australia
Site AT43005
Linz, , Austria
Site AT43001
Salzburg, , Austria
Site AT43004
Vienna, , Austria
Site BE32011
Aalst, , Belgium
Site BE32007
Brussels, , Belgium
Site BE32013
Brussels, , Belgium
Site BE32010
Charleroi, , Belgium
Site BE32001
Ghent, , Belgium
Site BE32008
Ghent, , Belgium
Site BE32005
Hasselt, , Belgium
Site BE32003
Leuven, , Belgium
Site BE32009
Liège, , Belgium
Site CA15015
Calgary, , Canada
Site CA15012
Edmonton, , Canada
Site CA15014
London, , Canada
Site CA15002
Montreal, , Canada
Site CA15007
Montreal, , Canada
Site CA15011
Oshawa, , Canada
Site CA15004
Québec, , Canada
Site CA15008
Saskatoon, , Canada
Site CA15001
Sherbrooke, , Canada
Site CA15005
Toronto, , Canada
Site CA15013
Vancouver, , Canada
Site DK45003
Aalborg, , Denmark
Site DK45004
Copenhagen, , Denmark
Site DK45001
Herlev, , Denmark
Site FR33021
Besançon, , France
Site FR33009
Bordeaux, , France
Site FR33018
Bordeaux, , France
Site FR33001
Brest, , France
Site FR33016
Caen, , France
Site FR33015
Lyon, , France
Site FR33014
Marseille, , France
Site FR33003
Nice, , France
Site FR33022
Paris, , France
Site FR33005
Pierre-Bénite, , France
Site FR33004
Saint-Mandé, , France
Site FR33002
Strasbourg, , France
Site FR33019
Toulouse, , France
Site FR33006
Villejuif, , France
Site DE49011
Essen, , Germany
Site DE49008
Heidelberg, , Germany
Site DE49010
Münster, , Germany
Site DE49003
Tübingen, , Germany
Site DE49009
Würzburg, , Germany
Site IT39008
Arezzo, , Italy
Site IT39019
Cremona, , Italy
Site IT39010
Milan, , Italy
Site IT39025
Modena, , Italy
Site IT39013
Pisa, , Italy
Site IT39014
Reggio Emilia, , Italy
Site IT39004
Terni, , Italy
Site JP81010
Hirosaki, Aomori, Japan
Site JP81014
Kashiwa, Chiba, Japan
Site JP81007
Sapporo, Hokkaido, Japan
Site JP81026
Sapporo, Hokkaido, Japan
Site JP81020
Tsukuba, Ibaraki, Japan
Site JP81018
Morioka, Iwate, Japan
Site JP81009
Kita-gun, Kagawa-ken, Japan
Site JP81002
Yokohama, Kanagawa, Japan
Site JP81005
Sendai, Miyagi, Japan
Site JP81016
Sayama, Osaka, Japan
Site JP81024
Takatsuki, Osaka, Japan
Site JP81008
Bunkyo-ku, Tokyo, Japan
Site JP81012
Koto-ku, Tokyo, Japan
Site JP81013
Shinjuku-ku, Tokyo, Japan
Site JP81011
Ube, Yamaguchi, Japan
Site JP81015
Chiba, , Japan
Site JP81019
Fukuoka, , Japan
Site JP81023
Fukuoka, , Japan
Site JP81004
Hiroshima, , Japan
Site JP81001
Kyoto, , Japan
Site JP81017
Niigata, , Japan
Site JP81003
Okayama, , Japan
Site JP81022
Osaka, , Japan
Site JP81021
Tokushima, , Japan
Site JP81006
Toyama, , Japan
Site NL31002
Amsterdam, , Netherlands
Site NL31003
Amsterdam, , Netherlands
Site NL31009
Nijmegen, , Netherlands
Site NL31001
Tilburg, , Netherlands
Site PT35102
Lisbon, , Portugal
Site PT35105
Lisbon, , Portugal
Site PT35106
Porto, , Portugal
Site RU70002
Ivanovo, , Russia
Site RU70009
Obninsk, , Russia
Site RU70005
Omsk, , Russia
Site RU70015
Vologda, , Russia
Site KR82006
Daejeon, , South Korea
Site KR82007
Goyang-si, , South Korea
Site KR82012
Hwasun-gun, , South Korea
Site KR82002
Incheon, , South Korea
Site KR82001
Seongnam-si, , South Korea
Site KR82003
Seoul, , South Korea
Site KR82004
Seoul, , South Korea
Site KR82008
Seoul, , South Korea
Site KR82009
Seoul, , South Korea
Site KR82010
Seoul, , South Korea
Site KR82005
Shin, , South Korea
Site ES34010
Badajoz, , Spain
Site ES34002
Badalona, , Spain
Site ES34001
Barcelona, , Spain
Site ES34012
Barcelona, , Spain
Site ES34023
Barcelona, , Spain
Site ES34014
Córdoba, , Spain
Site ES34003
Madrid, , Spain
Site ES34013
Madrid, , Spain
Site ES34015
Madrid, , Spain
Site ES34017
Madrid, , Spain
Site ES34011
Manresa, , Spain
Site ES34019
Pamplona, , Spain
Site ES34005
Seville, , Spain
Site ES34007
Valencia, , Spain
Site ES34008
Valencia, , Spain
Site CH41002
Bern, , Switzerland
Site CH41001
Chur, , Switzerland
Site TW88602
Kaohsiung City, , Taiwan
Site TW88605
Kaohsiung City, , Taiwan
Site TW88606
Taichung, , Taiwan
Site TW88601
Tainan, , Taiwan
Site TW88604
Taipei, , Taiwan
Site TW88607
Taoyuan District, , Taiwan
Site GB44005
London, , United Kingdom
Site GB44006
London, , United Kingdom
Site GB44004
Metropolitan Borough of Wirral, , United Kingdom
Site GB44002
Sheffield, , United Kingdom
Site GB44011
Southampton, , United Kingdom
Site GB44013
Sutton, , United Kingdom
Countries
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References
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Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengelov L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. doi: 10.1016/j.eururo.2024.01.007. Epub 2024 Feb 28.
Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. doi: 10.1056/NEJMoa2035807. Epub 2021 Feb 12.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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2017-003344-21
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
jRCT2080224027
Identifier Type: REGISTRY
Identifier Source: secondary_id
2024-517571-20-00
Identifier Type: REGISTRY
Identifier Source: secondary_id
7465-CL-0301
Identifier Type: -
Identifier Source: org_study_id
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