Treatment Combination of Durvalumab, Tremelimumab and Enfortumab Vedotin or Durvalumab and Enfortumab Vedotin in Patients With Muscle Invasive Bladder Cancer Ineligible to Cisplatin or Who Refuse Cisplatin (VOLGA)

A Phase III Randomized, Open-Label, Multicenter Study to Determine the Efficacy and Safety of Durvalumab in Combination With Tremelimumab and Enfortumab Vedotin or Durvalumab in Combination With Enfortumab Vedotin for Perioperative Treatment in Patients Ineligible for Cisplatin or Who Refuse Cisplatin Undergoing Radical Cystectomy for Muscle Invasive Bladder Cancer (VOLGA)

A global phase 3, multicenter, randomized, trial, to Determine the Efficacy and Safety of Durvalumab in combination with Tremelimumab and Enfortumab Vedotin or Durvalumab in combination with Enfortumab Vedotin for Perioperative Treatment in Patients Ineligible for Cisplatin or who refuse Cisplatin based chemotherapy Undergoing Radical Cystectomy for Muscle Invasive Bladder Cancer.

The goal of the study is to explore the triplet combination of Durvalumab, Tremelimumab and Enfortumab Vedotin or the duplet combination of Durvalumab and Enfortumab vedotin in terms of efficacy and safety compared to the current Standard Of Care (SOC).

VOLGA trial consists of two parts: Safety Run-In and Main Study. In total the study aims to enroll approximately 677 patients, who will receive triplet combination, duplet combination or currently approved SOC in the main study. In the main part of the trial there is two out of three chances of being on a treatment arm and the treatment is assigned at random by a computer system.

In this trial patients in the two treatment arms will receive either 3 cycles of neoadjuvant Durvalumab + Enfortumab Vedotin and 2 cycles of Tremelimumab or Durvalumab + Enfortumab vedotin and after surgery both treatment arms will receive either adjuvant Durvalumab or adjuvant Durvalumab and 1 cycle of Tremelimumab.

Study Overview

• Status: Active, not recruiting
• Conditions: Muscle Invasive Bladder Cancer
• Intervention / Treatment: Drug: Durvalumab; Drug: Tremelimumab; Drug: Enfortumab Vedotin; Procedure: Radical Cystectomy

Detailed Description

Not provided

• Study Type: Interventional
• Enrollment (Actual): 712
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1431FWO
    • Research Site
  • CABA, Argentina, C1426ANZ
    • Research Site
  • Ciudad de Buenos Aires, Argentina, C1419AHL
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  • Ciudad de Buenos Aires, Argentina, C1280AEB
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  • Pergamino, Argentina, B2700CPM
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• Austria
  • Graz, Austria, 8036
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  • Krems, Austria, 3500
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  • Linz, Austria, 4020
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  • Vienna, Austria, 1020
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  • Wiener Neustadt, Austria, 2700
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• Brazil
  • Barretos, Brazil, 14784-400
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  • Curitiba, Brazil, 81520-060
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  • Fortaleza, Brazil, 60135-237
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  • Porto Alegre, Brazil, 90035-003
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  • Porto Alegre, Brazil, 90035-001
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  • Rio de Janeiro, Brazil, 22250-905
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  • Santa Maria, Brazil, 97015-450
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  • São Paulo, Brazil, 01246-000
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  • São Paulo, Brazil, 01323-903
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  • Săo Paulo, Brazil, 03162-065
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  • Uberlândia, Brazil, 38408-150
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• Canada
  • British Columbia
    • Abbotsford British Columbia, British Columbia, Canada, V2S 3N5
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  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
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  • Quebec
    • Québec, Quebec, Canada, G1R 2J6
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    • Sherbrooke, Quebec, Canada, J1H 5N4
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• Chile
  • Santiago, Chile, 7500921
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  • Santiago, Chile, 7500653
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• France
  • Amiens, France, 80090
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  • Bayonne, France, 64100
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  • Clermont-Ferrand, France, 63011
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  • Lille, France, 59000
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  • Lyon, France, 69008
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  • Marseille, France, 13273
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  • Marseille, France, 13385
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  • Montpellier, France, 34070
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  • Nice, France, 06189
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  • Pierre-Bénite, France, 69495
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  • Quint-Fonsegrives, France, 31130
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  • Saint-Priez En Jarez, France, 42270
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  • Strasbourg, France, 67091
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  • Suresnes, France, 92151
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  • Vandœuvre-lès-Nancy, France, 54519
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• Germany
  • Bielefeld, Germany, 33611
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  • Bochum, Germany, 44791
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  • Cologne, Germany, 50937
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  • Düsseldorf, Germany, 40225
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  • Giessen, Germany, 35392
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  • Hanover, Germany, 30625
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  • Herne, Germany, 44625
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  • Magdeburg, Germany, 39120
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  • Mainz, Germany, 55131
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  • Mannheim, Germany, 68167
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  • München, Germany, 81377
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  • Münster, Germany, 48149
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  • Regensburg, Germany, 93053
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  • Reutlingen, Germany, 72766
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  • Ulm, Germany, 89075
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• Greece
  • Athens, Greece, 11528
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  • Athens, Greece, 12462
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  • Maroussi, Athens, Greece, 15125
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• Hong Kong
  • Shatin, Hong Kong, 00000
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• Israel
  • Hadera, Israel, 38100
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  • Haifa, Israel, 31096
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  • Jerusalem, Israel, 9112001
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  • Jerusalem, Israel, 9103102
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  • Tel Aviv, Israel, 64239
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• Italy
  • Bari, Italy, 70124
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  • Florence, Italy, 50134
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  • Meldola, Italy, 47014
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  • Milan, Italy, 20141
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  • Milan, Italy, 20132
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  • Padova, Italy, 35128
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  • Pozzuoli, Italy, 80078
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  • Reggio Emilia, Italy, 42100
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  • Roma, Italy, 00128
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  • Roma, Italy, 00144
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  • Roma, Italy, 00137
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  • Terni, Italy, 05100
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  • Tricase, Italy, 73039
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  • Verona, Italy, 37124
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• Japan
  • Bunkyō City, Japan, 113-8431
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  • Fukuoka, Japan, 811-1395
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  • Hamamatsu, Japan, 431-3192
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  • Ichikawa-shi, Japan, 272-8516
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  • Kanazawa, Japan, 920-8641
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  • Kashihara-shi, Japan, 634-8522
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  • Kawasaki-shi, Japan, 216-8511
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  • Kita-gun, Japan, 761-0793
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  • Kobe, Japan, 650-0017
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  • Kumamoto, Japan, 860-0008
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  • Matsuyama, Japan, 791-0288
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  • Miyazaki, Japan, 889-1692
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  • Niigata, Japan, 951-8566
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  • Okayama, Japan, 700-8558
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  • Osaka, Japan, 545-8586
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  • Osaka, Japan, 541-8567
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  • Osakasayama-shi, Japan, 589-8511
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  • Toyama, Japan, 930-0194
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  • Tsukuba, Japan, 305-8576
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  • Yokohama, Japan, 241-8515
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• Mexico
  • Colima, Mexico, 28018
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  • Monterrey, Mexico, 64000
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• Netherlands
  • Arnhem, Netherlands, 6815 AD
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  • Breda, Netherlands, 4818 CK
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  • Groningen, Netherlands, 9713 GZ
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  • Hoofddorp, Netherlands, 2134 TM
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  • Leiden, Netherlands, 2333 ZA
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  • Utrecht, Netherlands, 3508 GA
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• Poland
  • Gdansk, Poland, 80-214
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  • Nowa Sól, Poland, 67-106
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  • Skórzewo, Poland, 60-185
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  • Warsaw, Poland, 02-781
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• Portugal
  • Braga, Portugal, 4710
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  • Coimbra, Portugal, 3000-075
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  • Faro, Portugal, 8000-386
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  • Lisbon, Portugal, 1649-035
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  • Lisbon, Portugal, 1169-050
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  • Lisbon, Portugal, 1500-650
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  • Lisbon, Portugal, 1350-352
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  • Lisbon, Portugal, 1500-458
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• Serbia
  • Belgrade, Serbia, 11000
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  • Kamenitz, Serbia, 21204
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• South Korea
  • Busan, South Korea, 47392
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  • Goyang-si, South Korea, 10408
    • Research Site
  • Incheon, South Korea, 405-760
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  • Seongnam-si, South Korea, 13620
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  • Seoul, South Korea, 02841
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  • Seoul, South Korea, 03080
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  • Seoul, South Korea, 06351
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  • Seoul, South Korea, 06591
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  • Seoul, South Korea, 07985
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• Spain
  • Barcelona, Spain, 08035
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  • Barcelona, Spain, 08036
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  • Barcelona, Spain, 08041
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  • Barcelona, Spain, 08208
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  • L'Hospitalet de Llobregat, Spain, 08907
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  • Las Palmas de Gran Canaria, Spain, 35016
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  • Madrid, Spain, 28046
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  • Madrid, Spain, 28040
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  • Madrid, Spain, 28033
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  • Pamplona, Spain, 31008
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  • Seville, Spain, 41009
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• Taiwan
  • Taichung, Taiwan, 40705
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  • Taichung, Taiwan, 40447
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  • Tainan, Taiwan, 70403
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  • Tainan, Taiwan, 710
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• Thailand
  • Bangkok, Thailand, 10330
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  • Dusit, Thailand, 10300
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  • Songkhla, Thailand, 90110
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• Turkey (Türkiye)
  • Adana, Turkey (Türkiye), 01060
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  • Ankara, Turkey (Türkiye), 06620
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  • Ankara, Turkey (Türkiye), 06560
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  • Ankara, Turkey (Türkiye), 5000
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  • Ankara, Turkey (Türkiye)
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  • Antalya, Turkey (Türkiye), 07025
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  • Cordaleo, Turkey (Türkiye), 35575
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  • Edirne, Turkey (Türkiye), 22030
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  • Istanbul, Turkey (Türkiye), 34722
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  • Istanbul, Turkey (Türkiye), 32098
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• United Kingdom
  • London, United Kingdom, EC1A 7BE
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  • London, United Kingdom, NW1 2PG
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• United States
  • California
    • Orange, California, United States, 92868
      • Research Site
    • Santa Monica, California, United States, 90404
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  • Connecticut
    • New Haven, Connecticut, United States, 06510
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  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
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  • Florida
    • Fort Myers, Florida, United States, 33901
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  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
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  • Illinois
    • Maywood, Illinois, United States, 60153
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  • Indiana
    • Indianapolis, Indiana, United States, 46250
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  • Iowa
    • Iowa City, Iowa, United States, 52242
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  • Kentucky
    • Louisville, Kentucky, United States, 40207
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  • Maine
    • Scarborough, Maine, United States, 04074
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  • Massachusetts
    • Boston, Massachusetts, United States, 02111
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  • Michigan
    • Brighton, Michigan, United States, 48114
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  • Mississippi
    • Jackson, Mississippi, United States, 39213
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  • Nevada
    • Las Vegas, Nevada, United States, 89102
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  • New Jersey
    • Saddle Brook, New Jersey, United States, 07663
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  • New York
    • Brooklyn, New York, United States, 11219
      • Research Site
    • Buffalo, New York, United States, 14263
      • Research Site
    • New York, New York, United States, 10040
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    • Syracuse, New York, United States, 13210
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  • Oregon
    • Portland, Oregon, United States, 97239
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  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
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    • Pittsburgh, Pennsylvania, United States, 15212
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  • Tennessee
    • Knoxville, Tennessee, United States, 37932
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  • Texas
    • Austin, Texas, United States, 78731
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    • Dallas, Texas, United States, 75246
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    • Fort Worth, Texas, United States, 76104
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    • Houston, Texas, United States, 77030
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    • Irving, Texas, United States, 75063
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  • Virginia
    • Norfolk, Virginia, United States, 23502
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  • Washington
    • Spokane, Washington, United States, 99208
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• Vietnam
  • Hanoi, Vietnam, 100000
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  • Ho Chi Minh City, Vietnam, 700000
    • Research Site
  • Huế, Vietnam, 530000
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  • Hà Nội, Vietnam, 100000
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically documented muscle-invasive UC of the bladder.
• Participants with transitional cell and mixed transitional/non-transitional cell histologies;
• Participants with MIBC clinical tumor (T) stage T2-T4aN0/1M0 or UC of the bladder with clinical state T1N1M0 (participants with T1 stage are allowed only with N1 disease)
• Participants should also have not received prior systemic chemotherapy or immunotherapy for the treatment of MIBC or bladder UC.
• Medically fit for cystectomy and able to receive neoadjuvant therapy;
• Patients who have not received prior systemic chemotherapy or immunotherapy for treatment of MIBC;
• ECOG performance status of 0,1,2 at enrollment.
• Availability of tumor sample prior to study entry;
• Must have a life expectancy of at least 12 weeks at randomization.
• Cisplatin-ineligible, following criteria based on Galsky et al 2011 OR Refuse cisplatin based chemotherapy (must be documented in the medical records)

Exclusion criteria:

• Evidence of lymph node (N2+) or metastatic TCC/UC disease at the time of screening.
• Active infection
• Uncontrolled intercurrent illness
• Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette Guerin [BCG]), including but not limited to other anti-CTLA-4, anti--PD-1, anti PD-L1, or anti-PD-L2 antibodies.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of IPs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Durvalumab + Enfortumab vedotin; Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin, followed by radical cystectomy, followed by 9 cycles of Durvalumab. Each postoperative cycle is 28 days.	Drug: Durvalumab; Anti- PD-L1 Antibody; Other Names: MEDI4736; IMFINZI; Drug: Enfortumab Vedotin; Nectin-4-directed antibody and microtubule inhibitor conjugate; Other Names: PADCEV; Procedure: Radical Cystectomy; For cisplatin-ineligible or cisplatin-refusal patients
Active Comparator: Cystectomy with or without approved Adjuvant Therapy.; Participants may receive SoC (nivolumab approved as adjuvant treatment for MIBC based on high risk criteria) per approved label in the country OR Participants receive standard of care surgery (radical cystectomy) alone.	Procedure: Radical Cystectomy; For cisplatin-ineligible or cisplatin-refusal patients
Experimental: Durvalumab + Tremelimumab + Enfortumab Vedotin; Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin and 2 cycles of Tremelimumab, followed by radical cystectomy, followed by 1 cycle of postoperative Tremelimumab and 9 cycles of Durvalumab. Each postoperative cycle is 28 days.	Drug: Durvalumab; Anti- PD-L1 Antibody; Other Names: MEDI4736; IMFINZI; Drug: Tremelimumab; Human IgG2 mAb; Drug: Enfortumab Vedotin; Nectin-4-directed antibody and microtubule inhibitor conjugate; Other Names: PADCEV; Procedure: Radical Cystectomy; For cisplatin-ineligible or cisplatin-refusal patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin or who refuse cisplatin as assessed by abnormality in clinical chemistry by kidney function (Safety Run-In part)	Clinical chemistry will be assessed by kidney function assessment in mg/dL	Up to 84 months
Changes in WHO/ECOG performance status (Safety Run-In part)	Eastern Cooperative Oncology Group (ECOG) performance status scale range 0 to 5, where 0 is fully active, able to carry on all pre disease performance without restriction - best outcome and 5 -death - worst outcome.	Up to 84 months
To assess the safety and tolerability as evaluated by adverse events occurring throughout the study (Safety Run-In part)	Frequency of Adverse Events.	At completion of study treatment by the last patient and at 3 months.
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by vital signs (blood pressure in mmHg) (Safety Run-In part)		Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by vital signs (pulse rate) in beats per minute (Safety Run-In part)		Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by vital signs (respiration rate) in breaths per minute (Safety Run-In part)		Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by vital signs (temperature) in degrees Celsius (Safety Run-In part)		Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by abnormality in clinical chemistry by liver function (Safety Run-In part)	Clinical chemistry will be assessed by liver function assessment (ALT, AST, albumin, total bilirubin measured in units per dL)	Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by abnormality in clinical chemistry by thyroid function (Safety Run-In part)	Clinical chemistry will be assessed by thyroid function assessment in units per mL.	Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as assessed by abnormality in haematology (Safety Run-In part)	Hematology will be assessed by white cell count, platelet count, absolute neutrophil count and absolute lymphocyte count.	Up to 84 months
To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin as as assessed by ECG (pulse rate) (Safety Run-In part)		Up to 84 months
Compare efficacy of durvalumab + tremelimumab + EV (Arm 1) relative to cystectomy (Arm 3) and durvalumab + EV (Arm 2) relative to cystectomy (Arm 3) on EFS (Main Study)	Event-free survival (EFS;) is defined as the time from randomization to the first occurrence of any of the following events: recurrence of disease post-radical cystectomy, the first documented progression in participants who did not receive radical cystectomy, failure to undergo radical cystectomy in participants with residual disease, or death due to any cause, up to 3 years.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2. To evaluate the efficacy of durvalumab + tremelimumab + EV on EFS (Safety Run-in part)	Event-free survival (EFS;) is defined as the time from randomization to the first occurrence of any of the following events: recurrence of disease post-radical cystectomy, the first documented progression in participants who did not receive radical cystectomy, failure to undergo radical cystectomy in participants with residual disease, or death due to any cause, up to 3 years.	3 years
3. Pathologic complete response (pCR) rates at time of cystectomy in Arm1 vs Arm3 and Arm 2 vs Arm 3 (Main Study part)	Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per local pathological review using specimens obtained via cystectomy, at 3 years.	3 years
4. Overall survival (Safety Run-in and Main Study part)	Overall Survival is defined as length of time from randomization until the date of death due to any cause, whichever came first, assessed up to 5 years.	Up to 5 years
5. EFS at 24 months (EFS24) (Safety Run-in and Main Study part)	EFS24 is defined as proportion of participants alive and event-free at 24 months	Up to 24 months
6. Overall survival rate at 5 years (Safety Run-in and Main Study part)	The proportion of participants alive at 5 years (OS5) is defined as the Kaplan-Meier estimate of OS at 5 years after randomization	At 5 years
7. Disease-free survival (DFS) (Safety Run-in and Main Study part)	DFS is defined as time from radical cystectomy to recurrence or death, whichever came first, assessed up to 5 years.	Up to first recurrence of disease or death up to 5 years
8. Pathologic downstaging (pDS) rate-to < pT2 (Safety Run-in and Main Study part)	pDS rate is defined as the rate of downstaging to < pT2, including pT0, pTis, pTa, pT1, and N0	3 years
9. Disease-specific survival (DSS) (Safety Run-in and Main Study part)	DSS is defined as time from randomization until death due to bladder cancer, assessed up to 5 years.	from randomization until death due to bladder cancer up to 5 year.
10. EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire) (Safety Run-in and Main Study part)		from baseline and time to definitive clinically, assessed up to 5 years
11. Immunogenicity of durvalumab when used in combination with Tremelimumab as measured by presence of antidrug antibodies (ADA) (Safety Run-in and Main Study part)		At 3 months after last dose of durvalumab and tremelimumab
12. Time to maximum observed serum concentration (tmax) of durvalumab and tremelimumab (Safety Run-in and Main Study part)		At 3 months after last dose of durvalumab and tremelimumab
13. Metastasis-free survival (MFS) (Safety Run-in and Main Study part)	MFS is defined as the time from date of randomization until the first recognition of distant metastases or death, whichever occurs first, up to approximately 48 months.	From randomization until the first recognition of distant metastases or death, up to approximately 48 months.
1. To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate (Safety Run-in part)	Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per local pathology and central independent review using specimens obtained via cystectomy, at 3 years.	3 years

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2021
• Primary Completion (Actual): March 2, 2026
• Study Completion (Estimated): September 8, 2028

Study Registration Dates

• First Submitted: June 17, 2021
• First Submitted That Met QC Criteria: July 2, 2021
• First Posted (Actual): July 14, 2021

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; PD-L1; Durvalumab (MEDI4736); Bladder Cancer; Tremelimumab; Enfortumab Vedotin (PADCEV)
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Surgical Procedures, Operative; Urologic Surgical Procedures; Urogenital Surgical Procedures; durvalumab; enfortumab vedotin; tremelimumab; Cystectomy
• Other Study ID Numbers: D910PC00001; 2020-005452-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No