A Phase 3, Open-label, Randomized Study of Nivolumab Combined with Ipilimumab, or with Standard of Care Chemotherapy, versus Standard of Care Chemotherapy in Participants with Previously Untreated Unresectable or Metastatic Urothelial Cancer

The primary objective of this study is to compare **Overall Survival (OS)** of nivolumab combined with ipilimumab versus standard of care (SOC) chemotherapy in two specific cohorts: cisplatin-ineligible participants and PD-L1 positive (≥ 1%) participants, both with previously untreated, unresectable, or metastatic urothelial carcinoma (UC). This objective is clinically relevant as it aims to determine the efficacy of the combination therapy in improving survival outcomes in these patient populations, potentially offering a more effective treatment option for those who are unable to receive cisplatin or have PD-L1 positive tumors.

Secondary objectives include:

• Comparing OS of nivolumab combined with ipilimumab versus SOC chemotherapy in all randomized participants with previously untreated, unresectable, or metastatic UC.
• Evaluating **Progression-Free Survival (PFS)** of nivolumab combined with ipilimumab versus SOC chemotherapy in cisplatin-ineligible randomized participants, in PD-L1 positive (≥ 1%) randomized participants, and in all randomized participants with previously untreated, unresectable, or metastatic UC.
• Evaluating changes from baseline in Health-Related Quality of Life (HRQoL) of nivolumab combined with ipilimumab versus SOC chemotherapy in all randomized participants with previously untreated, unresectable, or metastatic UC.

The clinical trial involves a total of **1076 participants** diagnosed with **untreated unresectable 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 includes adults and older adults. Participants were selected based on specific criteria, including having metastatic or inoperable urothelial cancer, possessing at least one lesion with measurable disease, and having no prior systemic chemotherapy treatment in the metastatic setting. Additionally, participants must have full activity or, if limited, must be able to walk and carry out light activities such as light housework or office work. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

The clinical trial is a **randomized**, open-label, Phase 3 study designed to evaluate the efficacy of **nivolumab** combined with **ipilimumab** or standard of care chemotherapy in participants with previously untreated, unresectable, or metastatic **urothelial cancer**. The primary objective is to compare overall survival (OS) between the treatment groups, specifically in cisplatin-ineligible participants and those with PD-L1 positive tumors. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on June 30, 2017.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having metastatic or inoperable urothelial cancer and no prior systemic chemotherapy in the metastatic setting. Following randomization, participants will receive treatment according to their assigned group. The trial includes regular follow-up visits to monitor treatment response and safety, with assessments conducted by blinded independent central review using RECIST 1.1 criteria. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 126 days for those receiving chemotherapy and up to 84 days for those receiving nivolumab combined with ipilimumab. Participants may be withdrawn from the study early due to adverse events, disease progression, or withdrawal of consent. The trial's endpoints include primary endpoints of OS in specific subgroups and secondary endpoints such as progression-free survival (PFS) and quality of life assessments using the EORTC QLQ-C30 Global Health Status score.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **Nivolumab**, marketed as OPDIVO, which is a concentrate for solution for infusion. It contains the active substance **Nivolumab**, a protein-based therapeutic agent. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 480 mg, with a total dose not exceeding 4080 mg over the treatment period. The maximum treatment period for Nivolumab is 9999 days, and it is not a paediatric formulation.

Another experimental medication used in the trial is **Ipilimumab**, marketed as YERVOY. This is also a concentrate for solution for infusion, containing the active substance **Ipilimumab**, a protein-based therapeutic agent. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 3 mg/kg, with a total dose not exceeding 12 mg/kg over the treatment period. The maximum treatment period for Ipilimumab is 84 days, and it is not a paediatric formulation.

The trial also includes several comparator treatments, which are standard-of-care chemotherapies. **Carboplatin** is one such comparator, available in multiple formulations such as Carboplatin Bendalis, CARBO-cell, and Carbomedac, all of which are solutions for infusion. The active substance is **Carboplatin**, a chemical-based therapeutic agent. These formulations are administered intravenously, with a maximum daily dose of 5 mg and a total dose not exceeding 5 mg over the treatment period. The maximum treatment period for Carboplatin is 126 days.

**Cisplatin** is another comparator treatment, available in formulations such as Cisplatin Teva, Cisplatin NeoCorp, and CISPLATIN-EBEWE. These are solutions for infusion containing the active substance **Cisplatin**, a chemical-based therapeutic agent. The administration route is intravenous, with a maximum daily dose of 70 mg/m² and a total dose not exceeding 420 mg/m² over the treatment period. The maximum treatment period for Cisplatin is 126 days.

**Gemcitabine** is also used as a comparator treatment, available in formulations such as GEMCI-cell and Gemcitabine 38 mg/ml. These are concentrates for solution for infusion, containing the active substance **Gemcitabine**, a chemical-based therapeutic agent. The administration route is intravenous, with a maximum daily dose of 1000 mg/m² and a total dose not exceeding 12000 mg/m² over the treatment period. The maximum treatment period for Gemcitabine is 126 days.

All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to compare the overall survival of participants receiving Nivolumab combined with Ipilimumab versus those receiving standard-of-care chemotherapy in patients with previously untreated, unresectable, or metastatic urothelial cancer.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Overall Survival (OS)** in participants with previously untreated, unresectable, or metastatic urothelial carcinoma. The primary endpoints include OS in cisplatin-ineligible randomized participants and OS in PD-L1 positive (≥ 1%) randomized participants, as determined by immunohistochemistry (IHC). Secondary endpoints will include OS in all randomized participants, progression-free survival (PFS) by blinded independent central review (BICR) using RECIST 1.1 criteria, and the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status score in all randomized participants.

The trial will compare the efficacy of nivolumab combined with ipilimumab versus standard of care chemotherapy. The assessment of OS and PFS will be conducted at specified intervals throughout the trial, with the final analysis occurring at the end of the study. The EORTC QLQ-C30 Global Health Status score will be used to evaluate the quality of life in participants, providing a comprehensive measure of the treatment's impact on patient well-being. These efficacy parameters will be collected and analyzed to determine the comparative effectiveness of the treatment regimens under investigation.