Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer

A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination With Tremelimumab Versus Standard of Care Chemotherapy in Patients With Unresectable Stage IV Urothelial Cancer

A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination with Tremelimumab Versus Standard of Care Chemotherapy in Patients with Stage IV Urothelial Cancer

Study Overview

• Status: Active, not recruiting
• Conditions: Urothelial Cancer
• Intervention / Treatment: Drug: Gemcitabine; Drug: Carboplatin; Drug: Cisplatin; Drug: MEDI4736 (Durvalumab); Drug: Tremelimumab

Detailed Description

This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy and MEDI4736 (Durvalumab) in combination with tremelimumab versus SoC (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) first-line chemotherapy in treatment-naïve patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) and to allow sufficient flexibility for Investigators and patients to select the agents that reflect their normal clinical practice and national guidelines. The patients enrolled in the study will be randomized 1:1:1 to receive treatment with combination therapy, monotherapy, or SoC (cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility). Patients will be treated with MEDI4736 (Durvalumab) or MEDI4736 (Durvalumab) with tremelimumab, or treated with SoC until progressive disease (PD) is confirmed, unacceptable toxicity occurs, withdrawal of consent, or another discontinuation criterion is met. Patients will be followed for up to 2 years.

• Study Type: Interventional
• Enrollment (Actual): 1126
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Box Hill, Australia, 3128
    • Research Site
  • Elizabeth Vale, Australia, 5112
    • Research Site
  • Macquarie University, Australia, 2109
    • Research Site
  • St Leonards, Australia, 2065
    • Research Site
  • Waratah, Australia, 2298
    • Research Site
• Austria
  • Linz, Austria, 4010
    • Research Site
  • Wien, Austria, 1090
    • Research Site
  • Wien, Austria, 1140
    • Research Site
• Belgium
  • Brussels, Belgium, 1000
    • Research Site
  • Bruxelles, Belgium, 1200
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Liège, Belgium, 4000
    • Research Site
• Brazil
  • Barretos, Brazil, 14784-400
    • Research Site
  • Belo Horizonte, Brazil, 30380-472
    • Research Site
  • Ijui, Brazil, 98700-000
    • Research Site
  • Itajai, Brazil, 88310-110
    • Research Site
  • Porto Alegre, Brazil, 90035-003
    • Research Site
  • Porto Alegre, Brazil, 90610-000
    • Research Site
  • Porto Alegre, Brazil, 91350-200
    • Research Site
  • Rio de Janeiro, Brazil, 22793-080
    • Research Site
  • Rio de Janeiro, Brazil, 20231-050
    • Research Site
  • Sao Paulo, Brazil, 01321-001
    • Research Site
  • Sao Paulo, Brazil, 01509-900
    • Research Site
  • Sao Paulo, Brazil, 01209-000
    • Research Site
  • São José do Rio Preto, Brazil, 15090-000
    • Research Site
• Canada
  • Quebec, Canada, G1R 3S1
    • Research Site
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Research Site
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Research Site
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • Research Site
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Research Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Research Site
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Research Site
    • Newmarket, Ontario, Canada, L3Y 2P9
      • Research Site
    • Oshawa, Ontario, Canada, L1G 2B9
      • Research Site
    • Ottawa, Ontario, Canada, K1H 1C4
      • Research Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
    • Toronto, Ontario, Canada, M4N 3M5
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  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Research Site
• China
  • Beijing, China, 100034
    • Research Site
  • Beijing, China, 100191
    • Research Site
  • Beijing, China, 100039
    • Research Site
  • Changchun, China, 130012
    • Research Site
  • Changsha, China, 410013
    • Research Site
  • Chongqing, China, 400038
    • Research Site
  • Hangzhou, China, 310009
    • Research Site
  • Hangzhou, China, 310014
    • Research Site
  • Nanjing, China, 210008
    • Research Site
  • Shanghai, China, 200032
    • Research Site
  • Shanghai, China, 200080
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  • Shanghai, China, 200072
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  • Shanghai, China, 200000
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  • Shanghai, China, 200127
    • Research Site
  • Shenyang, China, 110001
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  • Tianjin, China, 300211
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  • Xi'an, China, 710061
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  • Xiamen, China, 361003
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• Denmark
  • Herlev, Denmark, 2730
    • Research Site
  • København Ø, Denmark, 2100
    • Research Site
  • Odense C, Denmark, 5000
    • Research Site
  • Århus C, Denmark, 8000
    • Research Site
• France
  • Bordeaux, France, 33076
    • Research Site
  • Bordeaux, France, 33000
    • Research Site
  • Caen Cedex, France, 14076
    • Research Site
  • Lyon Cedex 08, France, 69008
    • Research Site
  • Marseille cedex 09, France, 13273
    • Research Site
  • Paris Cedex 10, France, 75475
    • Research Site
  • Poitiers Cedex, France, 86021
    • Research Site
  • Suresnes Cedex, France, 92151
    • Research Site
  • Toulouse, France, 31059
    • Research Site
  • Villejuif, France, 94805
    • Research Site
• Germany
  • Düsseldorf, Germany, 40225
    • Research Site
  • Erlangen, Germany, 91054
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
  • Heidelberg, Germany, 69120
    • Research Site
  • Jena, Germany, 07747
    • Research Site
  • München, Germany, 81675
    • Research Site
  • Münster, Germany, 48149
    • Research Site
• Greece
  • Athens, Greece, 11528
    • Research Site
  • Heraklion, Greece, 71110
    • Research Site
  • Holargos, Athens, Greece, 155 62
    • Research Site
  • Kaliftaki, N.Kifissia, Athens, Greece, 14564
    • Research Site
  • Maroussi, Athens, Greece, 15125
    • Research Site
  • Patras, Greece, 26500
    • Research Site
  • Thessaloniki, Greece, 56 429
    • Research Site
• Israel
  • Haifa, Israel, 31096
    • Research Site
  • Jerusalem, Israel, 91120
    • Research Site
  • Petach-Tikva, Israel, 4941492
    • Research Site
  • Ramat Gan, Israel, 5265601
    • Research Site
  • Zerifin, Israel, 70300
    • Research Site
• Italy
  • Arezzo, Italy, 52100
    • Research Site
  • Meldola, Italy, 47014
    • Research Site
  • Milano, Italy, 20132
    • Research Site
  • Milano, Italy, 20133
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Orbassano, Italy, 10043
    • Research Site
  • Pavia, Italy, 27100
    • Research Site
  • Roma, Italy, 00152
    • Research Site
  • San Giovanni Rotondo, Italy, 71013
    • Research Site
• Japan
  • Akita-shi, Japan, 010-8543
    • Research Site
  • Bunkyo-ku, Japan, 113-8603
    • Research Site
  • Fukuoka-shi, Japan, 811-1347
    • Research Site
  • Hakata-shi, Japan, 812-0033
    • Research Site
  • Hirosaki-shi, Japan, 036-8563
    • Research Site
  • Hiroshima-shi, Japan, 730-8518
    • Research Site
  • Izumo-shi, Japan, 693-8501
    • Research Site
  • Kagoshima-shi, Japan, 890-8520
    • Research Site
  • Kanazawa-shi, Japan, 920-8641
    • Research Site
  • Kita-gun, Japan, 761-0793
    • Research Site
  • Kobe-shi, Japan, 650-0047
    • Research Site
  • Koshigaya-shi, Japan, 343-8555
    • Research Site
  • Koto-ku, Japan, 135-8550
    • Research Site
  • Kumamoto-shi, Japan, 860-0008
    • Research Site
  • Kyoto-shi, Japan, 606-8507
    • Research Site
  • Matsuyama-shi, Japan, 791-0280
    • Research Site
  • Morioka-shi, Japan, 028-3695
    • Research Site
  • Nagasaki-shi, Japan, 852-8501
    • Research Site
  • Nagoya-shi, Japan, 466-8560
    • Research Site
  • Nagoya-shi, Japan, 460-0001
    • Research Site
  • Osaka-shi, Japan, 541-8567
    • Research Site
  • Osaka-shi, Japan, 545-8586
    • Research Site
  • Osakasayama-shi, Japan, 589-8511
    • Research Site
  • Saga-shi, Japan, 840-8571
    • Research Site
  • Sagamihara-shi, Japan, 252-0315
    • Research Site
  • Sakura-shi, Japan, 285-8741
    • Research Site
  • Sapporo-shi, Japan, 060-8648
    • Research Site
  • Suita-shi, Japan, 565-0871
    • Research Site
  • Takatsuki-shi, Japan, 569-8686
    • Research Site
  • Yokohama-shi, Japan, 232-0024
    • Research Site
  • Yokohama-shi, Japan, 236-0004
    • Research Site
• Korea, Republic of
  • Incheon, Korea, Republic of, 21565
    • Research Site
  • Seongnam-si, Korea, Republic of, 13620
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 02841
    • Research Site
  • Seoul, Korea, Republic of, 6351
    • Research Site
• Mexico
  • Guadalajara, Mexico, 44280
    • Research Site
  • León, Mexico, 37000
    • Research Site
  • Mexico, Mexico, 06760
    • Research Site
  • Mexico, D.F, Mexico, 01120
    • Research Site
  • Monterrey, Mexico, 64460
    • Research Site
  • México, Mexico, 04739
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Research Site
  • Amsterdam, Netherlands, 1081 HV
    • Research Site
  • Breda, Netherlands, 4819 EV
    • Research Site
  • Enschede, Netherlands, 7512 KZ
    • Research Site
  • Groningen, Netherlands, 9713 GZ
    • Research Site
  • Leiden, Netherlands, 2333 ZA
    • Research Site
  • Maastricht, Netherlands, 6229 HX
    • Research Site
  • Nijmegen, Netherlands, 6525 GA
    • Research Site
• Poland
  • Gdańsk, Poland, 80-214
    • Research Site
  • Gdańsk, Poland, 80-462
    • Research Site
  • Gdynia, Poland, 81-519
    • Research Site
  • Gliwice, Poland, 44-101
    • Research Site
  • Olsztyn, Poland, 10-228
    • Research Site
  • Otwock, Poland, 05-400
    • Research Site
  • Szczecin, Poland, 70-111
    • Research Site
  • Warszawa, Poland, 02-781
    • Research Site
• Portugal
  • Lisboa, Portugal, 1649-035
    • Research Site
  • Loures, Portugal, 2674-514
    • Research Site
  • Porto, Portugal, 4099-001
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Research Site
  • Moscow, Russian Federation, 105229
    • Research Site
  • Murmansk, Russian Federation, 183047
    • Research Site
  • Nizhnyi Novgorod, Russian Federation, 603001
    • Research Site
  • Obninsk, Russian Federation, 249036
    • Research Site
  • Omsk, Russian Federation, 644013
    • Research Site
  • Saint Petersburg, Russian Federation, 191015
    • Research Site
  • Saint-Petersburg, Russian Federation, 197758
    • Research Site
  • St. Petersburg, Russian Federation, 194354
    • Research Site
  • St. Petersburg, Russian Federation, 199178
    • Research Site
  • St.Petersburg, Russian Federation, 191014
    • Research Site
  • Ufa, Russian Federation, 450054
    • Research Site
  • Yaroslavl, Russian Federation, 150054
    • Research Site
• Spain
  • Badajoz, Spain, 06008
    • Research Site
  • Badalona, Spain, 08916
    • Research Site
  • Barcelona, Spain, 08003
    • Research Site
  • Barcelona, Spain, 08243
    • Research Site
  • Elche(Alicante), Spain, 03202
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Madrid, Spain, 08035
    • Research Site
  • Madrid, Spain, 28050
    • Research Site
  • Madrid, Spain, 28007
    • Research Site
  • Pozuelo de Alarcon, Spain, 28223
    • Research Site
  • Santiago de Compostela, Spain, 15706
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
• Taiwan
  • Kaohsiung, Taiwan
    • Research Site
  • Taichung, Taiwan, 00407
    • Research Site
  • Tainan, Taiwan, 704
    • Research Site
  • Taipei, Taiwan, 10002
    • Research Site
  • Taipei, Taiwan, 112
    • Research Site
  • Taoyuan City, Taiwan, 333
    • Research Site
• Turkey
  • Ankara, Turkey, 06230
    • Research Site
  • Edirne, Turkey, 22030
    • Research Site
  • Izmir, Turkey, 35100
    • Research Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Research Site
  • Cardiff., United Kingdom, CF14 2TL
    • Research Site
  • Glasgow, United Kingdom, G12 0YN
    • Research Site
  • Leeds, United Kingdom, LS9 7TF
    • Research Site
  • London, United Kingdom, SE1 9RT
    • Research Site
  • London, United Kingdom, E1 1BB
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
  • Sheffield, United Kingdom, S10 2SJ
    • Research Site
  • Southampton, United Kingdom, SO16 6YD
    • Research Site
  • Wirral, United Kingdom, CH63 4JY
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Research Site
    • Stanford, California, United States, 94305
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Research Site
  • Florida
    • Tampa, Florida, United States, 33612
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Research Site
    • Detroit, Michigan, United States, 48201
      • Research Site
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Research Site
  • New York
    • New York, New York, United States, 10021
      • Research Site
    • New York, New York, United States, 10029
      • Research Site
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Research Site
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98101
      • 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:

• Patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma of the urothelium who have not been previously treated with first-line chemotherapy.
• Patients eligible or ineligible for cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting 1 of the following criteria: • Creatinine clearance (calculated or measured) <60 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or by measured 24-hour urine collection for determination • Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 audiometric hearing loss • CTCAE Grade ≥2 peripheral neuropathy • New York Heart Association ≥Class III heart failure.
• Tumor PD-L1 status, with Immunohistochemical (IHC) assay confirmed by a reference laboratory, must be known prior to randomization.

Exclusion Criteria:

• Prior exposure to immune-mediated therapy, including but not limited to, other anti cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment.
• History of allogenic organ transplantation that requires use of immunosuppressive agents.
• Active or prior documented autoimmune or inflammatory disorders. The following are exceptions to this criterion: • Patients with vitiligo or alopecia • Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement • Any chronic skin condition that does not require systemic therapy • Patients without active disease in the last 3 years may be included but only after consultation with AstraZeneca • Patients with celiac disease controlled by diet alone may be included but only after consultation with AstraZeneca.
• Brain metastases or spinal cord compression unless the patient's condition is stable and off steroids for at least 14 days prior to the start of study treatment. Patients with suspected or known brain metastases at screening should have an MRI (preferred)/CT, preferably with IV contrast to access baseline disease status.
• Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
• Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product (IP). The following are exceptions to this criterion: • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.

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: Combination Therapy; MEDI4736 (Durvalumab) + Tremelimumab	Drug: MEDI4736 (Durvalumab); IV infusion; Drug: Tremelimumab; IV infusion
Experimental: Monotherapy; MEDI4736 (Durvalumab)	Drug: MEDI4736 (Durvalumab); IV infusion
Active Comparator: Standard of Care; Standard of Care Chemotherapy Treatment	Drug: Gemcitabine; IV infusion; Drug: Carboplatin; IV infusion; Drug: Cisplatin; IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS, Full Analysis Set - Durvalumab Monotherapy vs SoC	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.	From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Alive at 24 Months (OS24), Full Analysis Set	Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.	From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
Alive at 24 Months (OS24), PD-L1-High Analysis Set	Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.	From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set	Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.	From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC	Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy	Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Alive and Progression-free at 12 Months (APF12), Full Analysis Set	Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set	Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set	Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.	Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC	Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.	Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy	Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.	Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC	Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy	Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population	Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR. unconfirmed responses are excluded.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (01NOV2017, a maximum of 3 years).
Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC	Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy	Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020)
Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC	Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy	Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Duration of Response (DoR), Full Analysis Set	Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Duration of Response (DoR), PD-L1-High Analysis Set	Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Duration of Response (DoR), PD-L1-Low/Negative Analysis Set	Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).	Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set	Blood samples were collected to determine the serum concentration of durvalumab.	Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.
Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set	Blood samples were collected to determine the serum concentration of tremelimumab.	Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.
Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients	Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Durvalumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.	At week 0, 4, 12 and 24, and at follow-up Month 3.
Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients	Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Tremelimumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.	At week 0, 4, 12 and at follow-up Month 3.
Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse outcome.	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC	Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.	At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bogemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suarez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. doi: 10.1016/S1470-2045(20)30541-6. Epub 2020 Sep 21. Erratum In: Lancet Oncol. 2021 Jan;22(1):e5.

Helpful Links

• Redacted SAP
• Redacted Protocol

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2015
• Primary Completion (Actual): January 27, 2020
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: July 13, 2015
• First Submitted That Met QC Criteria: August 4, 2015
• First Posted (Estimated): August 5, 2015

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Phase III; Urothelial Cancer
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Carboplatin; Durvalumab; Tremelimumab; Gemcitabine
• Other Study ID Numbers: D419BC00001; 2015-001633-24 (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 request 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