Phase 3 Randomized Trial of Neoadjuvant Chemotherapy with Nivolumab and BMS-986205 in Muscle-Invasive Bladder Cancer

The primary objective of this study is to compare the **pathological complete response (pCR)** rate of neoadjuvant nivolumab combined with gemcitabine and cisplatin (GC) to neoadjuvant GC alone in all randomized participants with muscle-invasive bladder cancer (MIBC). Additionally, the study aims to compare the event-free survival (EFS) of neoadjuvant nivolumab plus GC followed by continued nivolumab therapy after radical cystectomy (RC) versus neoadjuvant standard of care (SOC) GC followed by RC. These objectives are clinically relevant as they aim to evaluate the potential benefits of adding nivolumab to the standard chemotherapy regimen, which could lead to improved treatment outcomes for patients with MIBC.

Secondary objectives include:

• Comparing overall survival (OS) of neoadjuvant nivolumab plus GC followed by continued nivolumab therapy after RC versus neoadjuvant SOC GC followed by RC in all randomized participants.
• Describing the safety and tolerability of nivolumab and nivolumab in combination with GC chemotherapy.
• Comparing efficacy endpoints descriptively in all concurrently randomized patients across different treatment arms.

The clinical trial involves a total of **469 participants** diagnosed with **muscle-invasive bladder cancer** (MIBC). The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their clinical stage of T2-T4a, N0, M0, as diagnosed at transurethral resection of bladder tumor (TURBT) and confirmed by radiographic imaging. All participants must be eligible for radical cystectomy (RC) and have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are in relatively good health. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study aims to compare the pathological complete response (pCR) rate and event-free survival (EFS) between two treatment arms involving neoadjuvant therapies. Variant histology is acceptable if there is a predominant urothelial component.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of neoadjuvant chemotherapy alone versus neoadjuvant chemotherapy combined with **nivolumab** or nivolumab and BMS-986205, followed by post-surgery therapy in participants with muscle-invasive bladder cancer. The trial aims to compare the pathological complete response (pCR) rate and event-free survival (EFS) between the treatment arms. The study is expected to run until November 2027, with recruitment having commenced in January 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as clinical stage T2-T4a, N0, M0, and ECOG Performance Status 0 or 1. Following the screening, eligible participants will be randomized into one of the treatment arms. The trial includes multiple follow-up visits to monitor the participants' response to treatment and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.

The expected length of participant involvement in the trial is up to 48 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial's primary endpoints include the pCR rate and EFS, while secondary endpoints focus on overall survival, incidence of adverse events, and laboratory abnormalities. The study is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.

The clinical trial involves the administration of several treatments, including **gemcitabine hydrochloride**, marketed as GEMSOL, which is provided as a 40 mg/mL concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous use**. The maximum daily dose is 1000 mg/m², with a total maximum dose of 4000 mg/m² over a treatment period of up to 12 weeks. The product is manufactured by EBEWE PHARMA and will be over-labeled and repackaged for the trial without altering its composition or primary packaging.

Another treatment used in the trial is **nivolumab**, marketed as OPDIVO, available as a 10 mg/mL concentrate for solution for infusion. This treatment is also administered intravenously. The maximum daily dose is 480 mg, with a total maximum dose of 5760 mg over a treatment period of up to 48 weeks. The commercial bulk product is packaged, labeled, and released for clinical study use by BRISTOL-MYERS SQUIBB PHARMA EEIG.

**Cisplatin** is used in multiple formulations within the trial. One such formulation is Cisplatin NeoCorp, a 1 mg/mL concentrate for solution for infusion, provided by HEXAL AG. This product is administered intravenously with a maximum daily dose of 70 mg/m² and a total maximum dose of 280 mg/m² over a 12-week period. The product will be over-labeled and repackaged for the trial without changes to its composition or primary packaging.

Another formulation of **cisplatin** used is CISPLATIN-EBEWE, also a 1 mg/mL concentrate for solution for infusion, manufactured by EBEWE PHARMA. It shares the same dosing schedule and administration route as the Cisplatin NeoCorp formulation, with the same repackaging process for trial use.

The trial also includes Cisplatin Teva®, a 1 mg/mL concentrate for solution for infusion, provided by TEVA GMBH. This formulation is administered intravenously with identical dosing parameters and repackaging procedures as the other cisplatin formulations in the study.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Pathological Complete Response (pCR)** rate of neoadjuvant chemotherapy alone and neoadjuvant nivolumab plus chemotherapy, as well as the **Event-Free Survival (EFS)** of standard of care chemotherapy after radical cystectomy (RC) and neoadjuvant nivolumab plus chemotherapy followed by continued nivolumab after RC. Secondary endpoints encompass **Overall Survival (OS)**, the incidence of adverse events (AEs) and serious adverse events (SAEs), incidence of laboratory abnormalities, and further analysis of pCR rate, EFS, and OS as defined.

The trial is designed to compare the efficacy of neoadjuvant nivolumab plus gemcitabine and cisplatin (GC) to neoadjuvant GC alone in participants with muscle-invasive bladder cancer (MIBC). The efficacy parameters will be measured and collected at specified timepoints throughout the trial, with the final analysis conducted at the end of the treatment period. The trial is structured to ensure rigorous assessment of these endpoints to determine the comparative efficacy of the treatment regimens under investigation.