Efficacy and Safety of Durvalumab and Bacillus Calmette-Guérin in High-Risk, BCG-Naïve Non-Muscle Invasive Bladder Cancer: A Phase III Randomized Study

The primary objective of this study is to evaluate the **efficacy** of the combination therapy of **Durvalumab** and **Bacillus Calmette-Guérin (BCG)** compared to BCG alone in terms of **Disease-Free Survival (DFS)** in patients with high-risk, BCG-naïve non-muscle invasive bladder cancer. This is clinically relevant as improving DFS can potentially delay or prevent the progression of bladder cancer, thereby enhancing patient outcomes and reducing the need for more invasive treatments.

Secondary objectives include:

• Assessing the efficacy of the combination therapy compared to standard of care (SoC) in terms of disease-free survival at 24 months (DFS24), overall survival at 5 years (OS5), any disease-free survival (aDFS), time to muscle-invasive bladder cancer or metastatic disease, time to cystectomy, and time to development of upper tract urothelial carcinoma.
• Evaluating the efficacy of the combination therapy for patients with carcinoma in situ (CIS) prior to study entry or at baseline in terms of complete response rate (CRR) at 6 months.
• Assessing disease-related symptoms and health-related quality of life (HRQoL) in patients treated with the combination therapy compared to SoC using EORTC QLQ-C30 and EORTC QLQ NMIBC24.
• Evaluating tolerability using patient-reported PRO CTCAE symptoms.
• Assessing the pharmacokinetics (PK) and immunogenicity of Durvalumab.

The clinical trial involves a total of **560 participants** diagnosed with **non-muscle invasive bladder 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 being BCG-naïve or having ceased BCG treatment more than three years prior to study entry. The trial targets individuals with high-risk transitional cell carcinoma of the urothelium confined to the mucosa or submucosa, with complete resection of all Ta/T1 papillary disease required prior to randomization. The study does not include individuals with prior radiotherapy for bladder cancer or those previously exposed to immune-mediated cancer therapies. The trial population is characterized by a vulnerable group, indicating a need for careful monitoring and ethical considerations. Lifestyle factors such as diet and physical activity were not specified by the sponsor.

The clinical trial is designed as a **randomized**, open-label, multi-center, global study to evaluate the efficacy and safety of **durvalumab** in combination with intravesical **Bacillus Calmette-Guérin (BCG)** for the treatment of patients diagnosed with early-stage **non-muscle invasive bladder cancer**. The trial aims to compare this combination therapy against the standard therapy of intravesical BCG alone. The primary objective is to assess the efficacy in terms of disease-free survival (DFS), with secondary endpoints including disease-free survival at 24 months, overall survival at 5 years, complete response rate, and time to muscle-invasive bladder cancer or metastasis, among others.

The trial will span an estimated duration from January 2024 to September 2025. Participants will be involved for a maximum treatment period of 12 months. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as being BCG-naïve and having a high-risk transitional cell carcinoma of the urothelium, followed by regular follow-up visits to monitor treatment efficacy and safety. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it necessary for the participant's safety. The trial will employ a rigorous methodology to ensure the reliability and validity of the results, contributing valuable data to the understanding of treatment options for non-muscle invasive bladder cancer.

The clinical trial involves several treatments, including **MYCOPHENOLATE MOFETIL**, which is administered as a hard capsule. This medication is an immunosuppressive agent with a chemical origin. The route of administration is oral, and the treatment period is up to 12 months. The specific dosage and frequency of administration are not detailed in the provided data.

**INFLIXIMAB** is another treatment used in the trial, provided as a powder for concentrate for solution for infusion. It is administered via intravenous infusion. The treatment period is also up to 12 months. The exact dosage and frequency are not specified in the available information.

A **Placebo** is included in the study, although specific details regarding its pharmaceutical form, route of administration, and dosing schedule are not provided. The placebo serves as a comparator treatment in the trial.

**DURVALUMAB** is administered as a concentrate for solution for infusion, with a maximum total dose of 1500 mg. It is given intravenously, and the treatment period extends up to 12 months. This medication is of protein origin and is used in combination therapy within the trial.

**IMFINZI 50 mg/mL**, another form of **DURVALUMAB**, is also used in the trial. It is a concentrate for solution for infusion, administered intravenously, with a maximum total dose of 1500 mg over a 12-month period. This formulation is specifically noted as a pediatric formulation.

**OncoTICE®**, containing **BACILLUS CALMETTE-GUÉRIN (BCG), TICE**, is provided as a powder for instillation fluid for intravesical use. It is administered intravesically, with a treatment period that can extend indefinitely. This vaccine is used as a standard-of-care therapy in the trial.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of **Disease-Free Survival (DFS)**. This will involve comparing the combination therapy of durvalumab and Bacillus Calmette-Guérin (BCG) against BCG alone in patients with high-risk, BCG-naïve non-muscle invasive bladder cancer. Secondary endpoints include disease-free survival at 24 months (DFS24), overall survival at 5 years (OS5), complete response rate (CRR), any disease-free survival (aDFS), time to muscle-invasive bladder cancer or metastasis, time to cystectomy, and time to development of upper tract urothelial carcinoma (UTUC). Additionally, patient-reported treatment tolerability, pharmacokinetics (PK) of durvalumab, and immunogenicity of durvalumab (ADA) in combination with BCG will be assessed.

The efficacy parameters will be measured and collected at various timepoints throughout the trial, with specific attention to the primary endpoint of DFS. The analysis will be conducted using appropriate statistical methods to determine the comparative efficacy of the treatment regimens. The trial is designed to provide comprehensive data on the efficacy of the combination therapy in extending disease-free survival and improving overall patient outcomes in this specific patient population.