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

NCT ID: NCT02516241

Last Updated: 2026-01-28

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 1126 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-11-02
• Study Completion Date: 2026-12-31

Brief Summary

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

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.

Conditions

Urothelial Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Combination Therapy

MEDI4736 (Durvalumab) + Tremelimumab

Group Type: EXPERIMENTAL

MEDI4736 (Durvalumab)

Intervention Type: DRUG

IV infusion

Tremelimumab

Intervention Type: DRUG

IV infusion

Monotherapy

MEDI4736 (Durvalumab)

Group Type: EXPERIMENTAL

MEDI4736 (Durvalumab)

Intervention Type: DRUG

IV infusion

Standard of Care

Standard of Care Chemotherapy Treatment

Group Type: ACTIVE_COMPARATOR

Cisplatin

Intervention Type: DRUG

IV infusion

Carboplatin

Intervention Type: DRUG

IV infusion

Gemcitabine

Intervention Type: DRUG

IV infusion

Interventions

MEDI4736 (Durvalumab)

IV infusion

Intervention Type: DRUG

Tremelimumab

IV infusion

Intervention Type: DRUG

Cisplatin

IV infusion

Intervention Type: DRUG

Carboplatin

IV infusion

Intervention Type: DRUG

Gemcitabine

IV infusion

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Research Site

Los Angeles, California, United States

Research Site

Stanford, California, United States

Research Site

Aurora, Colorado, United States

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New Haven, Connecticut, United States

Research Site

Tampa, Florida, United States

Research Site

Atlanta, Georgia, United States

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Louisville, Kentucky, United States

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Boston, Massachusetts, United States

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Ann Arbor, Michigan, United States

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Detroit, Michigan, United States

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Omaha, Nebraska, United States

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New York, New York, United States

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New York, New York, United States

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Memphis, Tennessee, United States

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Nashville, Tennessee, United States

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Seattle, Washington, United States

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Box Hill, , Australia

Research Site

Elizabeth Vale, , Australia

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Macquarie University, , Australia

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St Leonards, , Australia

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Waratah, , Australia

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Linz, , Austria

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Vienna, , Austria

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Vienna, , Austria

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Brussels, , Belgium

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Brussels, , Belgium

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Leuven, , Belgium

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Liège, , Belgium

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Barretos, , Brazil

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Belo Horizonte, , Brazil

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Ijuí, , Brazil

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Itajaí, , Brazil

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Porto Alegre, , Brazil

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Porto Alegre, , Brazil

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Porto Alegre, , Brazil

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Rio de Janeiro, , Brazil

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Rio de Janeiro, , Brazil

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São José do Rio Preto, , Brazil

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São Paulo, , Brazil

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São Paulo, , Brazil

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São Paulo, , Brazil

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Calgary, Alberta, Canada

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Edmonton, Alberta, Canada

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Kelowna, British Columbia, Canada

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Vancouver, British Columbia, Canada

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Halifax, Nova Scotia, Canada

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Hamilton, Ontario, Canada

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Newmarket, Ontario, Canada

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Oshawa, Ontario, Canada

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Ottawa, Ontario, Canada

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Toronto, Ontario, Canada

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Toronto, Ontario, Canada

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Québec, Quebec, Canada

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Sherbrooke, Quebec, Canada

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Beijing, , China

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Beijing, , China

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Beijing, , China

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Changchun, , China

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Changsha, , China

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Chongqing, , China

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Hangzhou, , China

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Hangzhou, , China

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Nanjing, , China

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Shanghai, , China

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Shanghai, , China

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Shanghai, , China

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Shanghai, , China

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Shanghai, , China

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Shenyang, , China

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Tianjin, , China

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Xi'an, , China

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Xiamen, , China

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Århus C, , Denmark

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Herlev, , Denmark

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København Ø, , Denmark

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Odense C, , Denmark

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Bordeaux, , France

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Bordeaux, , France

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Caen, , France

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Lyon, , France

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Marseille, , France

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Paris, , France

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Poitiers, , France

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Suresnes, , France

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Toulouse, , France

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Villejuif, , France

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Düsseldorf, , Germany

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Erlangen, , Germany

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Hanover, , Germany

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Heidelberg, , Germany

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Jena, , Germany

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München, , Germany

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Münster, , Germany

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Athens, , Greece

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Athens, , Greece

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Heraklion, , Greece

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Holargos, Athens, , Greece

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Maroussi, Athens, , Greece

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Pátrai, , Greece

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Thessaloniki, , Greece

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Haifa, , Israel

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Jerusalem, , Israel

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Petah Tikva, , Israel

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Ramat Gan, , Israel

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Ẕerifin, , Israel

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Arezzo, , Italy

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Meldola, , Italy

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Milan, , Italy

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Milan, , Italy

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Napoli, , Italy

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Orbassano, , Italy

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Pavia, , Italy

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Roma, , Italy

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San Giovanni Rotondo, , Italy

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Akita, , Japan

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Bunkyō City, , Japan

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Fukuoka, , Japan

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Hakata-shi, , Japan

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Hirosaki-shi, , Japan

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Hiroshima, , Japan

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Izumo-shi, , Japan

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Kagoshima, , Japan

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Kanazawa, , Japan

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Kita-gun, , Japan

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Kobe, , Japan

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Koshigaya-shi, , Japan

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Kōtoku, , Japan

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Kumamoto, , Japan

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Kyoto, , Japan

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Matsuyama, , Japan

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Morioka, , Japan

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Nagasaki, , Japan

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Nagoya, , Japan

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Nagoya, , Japan

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Osaka, , Japan

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Osaka, , Japan

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Osakasayama-shi, , Japan

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Saga, , Japan

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Sagamihara-shi, , Japan

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Sakura-shi, , Japan

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Sapporo, , Japan

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Suita-shi, , Japan

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Takatsuki-shi, , Japan

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Yokohama, , Japan

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Yokohama, , Japan

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Guadalajara, , Mexico

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León, , Mexico

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Mexico City, , Mexico

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México, , Mexico

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México, , Mexico

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Monterrey, , Mexico

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Amsterdam, , Netherlands

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Amsterdam, , Netherlands

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Breda, , Netherlands

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Enschede, , Netherlands

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Groningen, , Netherlands

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Leiden, , Netherlands

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Maastricht, , Netherlands

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Nijmegen, , Netherlands

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Gdansk, , Poland

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Gdansk, , Poland

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Gdynia, , Poland

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Gliwice, , Poland

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Olsztyn, , Poland

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Otwock, , Poland

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Szczecin, , Poland

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Warsaw, , Poland

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Lisbon, , Portugal

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Loures, , Portugal

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Porto, , Portugal

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Moscow, , Russia

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Moscow, , Russia

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Murmansk, , Russia

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Nizhnyi Novgorod, , Russia

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Obninsk, , Russia

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Omsk, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Ufa, , Russia

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Yaroslavl, , Russia

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Incheon, , South Korea

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Seongnam-si, , South Korea

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Seoul, , South Korea

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Seoul, , South Korea

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Seoul, , South Korea

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Seoul, , South Korea

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Seoul, , South Korea

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Badajoz, , Spain

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Badalona, , Spain

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Barcelona, , Spain

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Barcelona, , Spain

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Elche(Alicante), , Spain

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Madrid, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Pozuelo de Alarcón, , Spain

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Santiago de Compostela, , Spain

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Seville, , Spain

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Kaohsiung City, , Taiwan

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Taichung, , Taiwan

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Tainan, , Taiwan

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Taipei, , Taiwan

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Taipei, , Taiwan

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Taoyuan, , Taiwan

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Ankara, , Turkey (Türkiye)

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Edirne, , Turkey (Türkiye)

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Izmir, , Turkey (Türkiye)

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Cambridge, , United Kingdom

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Cardiff, , United Kingdom

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Glasgow, , United Kingdom

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Leeds, , United Kingdom

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London, , United Kingdom

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London, , United Kingdom

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Manchester, , United Kingdom

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Metropolitan Borough of Wirral, , United Kingdom

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Sheffield, , United Kingdom

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Southampton, , United Kingdom

Countries

United States; Australia; Austria; Belgium; Brazil; Canada; China; Denmark; France; Germany; Greece; Israel; Italy; Japan; Mexico; Netherlands; Poland; Portugal; Russia; South Korea; Spain; Taiwan; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: DERIVED

PMID: 32971005 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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Redacted SAP

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Redacted Protocol

Other Identifiers

2015-001633-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D419BC00001

Identifier Type: -

Identifier Source: org_study_id