Phase III Randomized Study of Durvalumab, Tremelimumab, and Chemotherapy in Unresectable Locally Advanced or Metastatic Urothelial Carcinoma

The primary objective of this study is to evaluate the **efficacy** of durvalumab in combination with standard of care (SoC) chemotherapy, and durvalumab combined with tremelimumab and SoC chemotherapy, compared to SoC chemotherapy alone. This evaluation is focused on overall survival (OS) in patients with unresectable locally advanced or metastatic urothelial cancer (UC) who exhibit high PD-L1 expression. The clinical relevance of this objective lies in determining the potential survival benefits of these combination therapies over the current standard treatment, which could inform treatment decisions and improve patient outcomes in this population.

Secondary objectives include:

• Assessing the efficacy in patients across different treatment arms.
• Evaluating disease-related symptoms, safety, physical functioning, and other health-related quality of life measures in patients in different treatment arms.

The clinical trial involves a total of **921 participants** diagnosed with **unresectable locally advanced or metastatic urothelial cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a histological or cytological confirmation of transitional cell carcinoma of the urothelium, and they must not have received prior first-line chemotherapy. The trial includes individuals with a World Health Organization/Eastern Cooperative Oncology Group performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate organ and marrow function and a life expectancy of at least 12 weeks. The study also considers lifestyle factors such as post-menopausal status or a negative pregnancy test for pre-menopausal females. The trial population includes vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics.

The clinical trial is a **Phase III**, randomized, open-label, controlled, multi-center study designed to evaluate the efficacy of **durvalumab** in combination with standard-of-care chemotherapy, with or without **tremelimumab**, compared to standard-of-care chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer. The trial aims to assess overall survival (OS) as the primary endpoint, with secondary endpoints including progression-free survival (PFS), overall response rate (ORR), and safety among others. The study is expected to commence recruitment on May 31, 2024, and conclude by August 30, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically documented transitional cell carcinoma, adequate organ function, and a WHO/ECOG performance status of 0 or 1. Following randomization, participants will receive treatment according to their assigned group. Regular follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement varies depending on the treatment arm, with a maximum treatment period of up to 19 months for some regimens. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will utilize intravenous administration for most investigational products, with **mycophenolate mofetil** being administered orally. The study is not categorized as low intervention and is conducted in accordance with regulatory standards to ensure the safety and well-being of participants.

The clinical trial involves the administration of several treatments, including **IMJUDO** (tremelimumab), which is provided as a 20 mg/mL concentrate for solution for infusion. This experimental medication is administered intravenously. The maximum treatment period for IMJUDO is 12 months. The pharmaceutical form is a sterile concentrate, and it is not a pediatric formulation. The active substance, tremelimumab, is a protein of other origin, and the product is authorized in the EU under the marketing authorization number EU/1/22/1713/001.

Another experimental treatment in the trial is **IMFINZI** (durvalumab), available as a 50 mg/mL concentrate for solution for infusion. This medication is also administered intravenously. The maximum treatment period for IMFINZI is not specified, indicating continuous administration as needed. Durvalumab is a protein of other origin, and the product is authorized in the EU with the marketing authorization number EU/1/18/1322/001.

The trial includes the use of **GEMCITABINE**, which is provided in two forms: as a powder for solution for infusion and as a concentrate for solution for infusion. Both forms are administered intravenously. The maximum treatment period for gemcitabine is 19 months. The active substance, gemcitabine, is of chemical origin.

**CARBOPLATIN** is another treatment used in the study, available as a concentrate for solution for infusion. It is administered intravenously, with a maximum treatment period of 18 months. The active substance, carboplatin, is of chemical origin.

**CISPLATIN** is also included in the trial, provided as a concentrate for solution for infusion and administered intravenously. The maximum treatment period for cisplatin is 18 months. The active substance, cisplatin, is of chemical origin.

**MYCOPHENOLATE MOFETIL** is used as an auxiliary treatment in the trial. It is available in capsule form and administered orally. The maximum treatment period for mycophenolate mofetil is 12 months. The active substance is of chemical origin, and it is classified as an immunosuppressive agent.

**INFLIXIMAB** is another auxiliary treatment, provided as a powder for concentrate for solution for infusion. It is administered intravenously, with a maximum treatment period of 12 months. The active substance, infliximab, is a protein.

The efficacy of the clinical trial will be assessed using the primary endpoint of **Overall Survival (OS)**. Secondary endpoints include **Progression Free Survival (PFS)**, **Overall Response Rate (ORR)**, **Disease Control Rate (DCR)**, **Duration of Response (DoR)**, and other related measures such as **Alive and Progression Free Patients at 12 Months (APF12)**, **Time from Randomization to Second Progression PFS (PFS2)**, and safety assessments. The trial will evaluate the efficacy of **durvalumab** in combination with standard of care (SoC) chemotherapy, and **durvalumab** with **tremelimumab** plus SoC chemotherapy, compared to SoC chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer with high PD-L1 expression.

Data collection will occur at specified intervals throughout the trial, with the primary focus on measuring OS. The trial will utilize validated scales and laboratory tests to assess these endpoints. The efficacy parameters will be analyzed at various timepoints, including the end of treatment, to determine the effectiveness of the treatment regimens. The trial is designed to provide comprehensive data on the efficacy of the combination therapies in improving survival outcomes for patients with this condition.