Efficacy and Safety of Durvalumab, Tremelimumab, and Enfortumab Vedotin in Perioperative Treatment of Cisplatin-Ineligible Muscle Invasive Bladder Cancer

The primary objective of this Phase III randomized, open-label, multicenter study is to assess the **safety** and tolerability of the combination of durvalumab, tremelimumab, and enfortumab vedotin (EV) in participants with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin. Additionally, the study aims to compare the efficacy of durvalumab combined with tremelimumab and EV (Arm 1) relative to cystectomy (Arm 3), and durvalumab combined with EV (Arm 2) relative to cystectomy (Arm 3) on event-free survival (EFS). This is clinically relevant as it explores alternative treatment options for patients unable to undergo standard cisplatin-based therapy, potentially improving outcomes in this patient population.

Secondary objectives include:

• Evaluating the efficacy of durvalumab, tremelimumab, and EV on pathological complete response (pCR) rate and EFS during the Safety Run-In phase.
• Comparing the efficacy of the treatment combinations on various endpoints such as pCR rate, EFS, overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS).
• Assessing disease-related symptoms, functioning, and global health status/quality of life in participants treated with the study drugs compared to cystectomy.
• Evaluating the pharmacokinetics (PK) and immunogenicity of durvalumab and tremelimumab.
• Assessing the safety and tolerability of the treatment combinations in participants with MIBC who are ineligible for or refuse cisplatin.

The clinical trial involves a total of **393 participants** diagnosed with **bladder cancer**, specifically muscle-invasive transitional cell carcinoma (TCC) or urothelial carcinoma (UC) of the bladder. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult and older adult participants. The trial population was selected based on specific inclusion criteria, such as having histologically or cytologically documented muscle-invasive TCC or UC, and being medically fit for cystectomy. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at enrollment and must be ineligible for cisplatin-based chemotherapy. The study also considers lifestyle factors, as participants must not have received prior systemic chemotherapy or immunotherapy for the treatment of muscle-invasive bladder cancer. The trial includes a vulnerable population, ensuring a comprehensive assessment of the safety and efficacy of the investigational treatments.

The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the efficacy and safety of **durvalumab** in combination with **tremelimumab** and **enfortumab vedotin** for the perioperative treatment of patients with muscle-invasive bladder cancer who are ineligible for or refuse **cisplatin**. The trial is structured into two main components: a Safety Run-In (SRI) phase and a Main Study phase. The SRI phase aims to assess the safety and tolerability of the combination therapy, while the Main Study phase focuses on comparing the efficacy of the combination therapies against radical cystectomy alone. The trial is expected to run until September 2028, with recruitment having started in July 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically documented muscle-invasive transitional cell carcinoma of the bladder, ECOG performance status, and cisplatin ineligibility. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including adverse events, vital signs, and laboratory assessments. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 54 weeks, depending on individual treatment response and progression.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The primary endpoints include safety and tolerability in the SRI phase and event-free survival (EFS) in the Main Study phase. Secondary endpoints encompass pathologic complete response rate, overall survival, and disease-free survival, among others. The trial's design ensures rigorous monitoring and evaluation of the investigational therapies' impact on bladder cancer treatment outcomes.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Durvalumab** is provided as a concentrate for solution for infusion. It is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1κ) subclass that inhibits the binding of programmed cell death ligand 1 (PD-L1) to programmed cell death 1 (PD-1) and CD80. The maximum total dose for durvalumab is 18,000 mg, administered intravenously over a treatment period of up to 54 weeks.

**Tremelimumab** is also administered as a concentrate for solution for infusion. It is a monoclonal antibody targeting CTLA-4, a protein receptor that downregulates the immune system. The maximum total dose for tremelimumab is 225 mg, delivered intravenously over the same treatment period of 54 weeks.

**Enfortumab vedotin** is provided in two formulations: Padcev 30 mg and Padcev 20 mg, both as powder for concentrate for solution for infusion. Enfortumab vedotin is an antibody-drug conjugate targeting Nectin-4, a protein highly expressed in several cancers. The maximum total dose is 750 mg, administered intravenously, with a maximum daily dose of 1.25 mg/kg, over a 54-week period.

**Infliximab** is included as a biological product, administered intravenously. It is a chimeric monoclonal antibody against tumor necrosis factor alpha (TNFα), used in various inflammatory conditions. The maximum total dose for infliximab is 100 mg, with the treatment period extending up to 54 weeks.

**Mycophenolate mofetil** is administered orally as a chemical compound. It is an immunosuppressant used to prevent organ rejection in transplant patients. The maximum total dose is 250 mg, with the treatment period lasting up to 54 weeks.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these medications in combination for the perioperative treatment of patients with muscle invasive bladder cancer who are ineligible for or refuse cisplatin.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint for the main study is Event-Free Survival (EFS), which 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. This will be evaluated per Blinded Independent Central Review (BICR) or by central pathology review if a biopsy is required for a suspected new lesion.

Secondary endpoints include the pathologic complete response (pCR) rate, defined as the number of participants whose pathological staging was T0N0M0 as assessed per local pathological review using specimens obtained via cystectomy. Other secondary endpoints include Overall Survival (OS), Disease-Free Survival (DFS), and the proportion of participants alive and event-free at 24 months (EFS24). Additionally, the study will assess the rate of downstaging to less than pT2, Disease-Specific Survival (DSS), and Metastasis-Free Survival (MFS). The study will also evaluate the adjusted mean change from baseline and time to definitive clinically meaningful deterioration in EORTC QLQ-C30 scale/item scores, focusing on domains such as fatigue, pain, physical functioning, and global health status/Quality of Life (QoL).

Concentration of **durvalumab** and **tremelimumab** in serum and pharmacokinetic (PK) parameters will be measured, along with the presence of anti-drug antibodies (ADAs) for these agents. Safety and tolerability will be evaluated in terms of adverse events (AEs), vital signs, clinical laboratory assessments, electrocardiograms (ECGs), and WHO/ECOG performance status, as described for the corresponding safety run-in objectives and endpoints.