Randomized, Double-Blind Phase 3b Study of Nivolumab Plus Ipilimumab Versus Nivolumab Monotherapy in Untreated Advanced Renal Cell Carcinoma with Intermediate or Poor Risk

The primary objective of this study is to compare the **Progression-Free Survival (PFS)** and **Overall Response Rate (ORR)** using RECIST 1.1 criteria between two treatment regimens: nivolumab combined with ipilimumab versus nivolumab and placebo in all randomized participants with advanced renal cell carcinoma. This comparison is clinically relevant as it aims to determine the efficacy of the combination therapy in delaying disease progression and improving response rates, which are critical endpoints in the management of advanced renal cell carcinoma.

Secondary objectives include:

• Comparing the **Overall Survival (OS)** of nivolumab combined with ipilimumab versus nivolumab and placebo in all randomized participants.
• Evaluating additional efficacy measures in all randomized participants.
• Estimating the incidence of **Adverse Events (AEs)** associated with the treatment regimens in all treated participants.
• Investigating whether gene expression signatures related to clear cell renal cell carcinoma (ccRCC) enhance clinical benefit with the treatment regimens.
• Exploring the association of baseline **PD-L1 expression** on tumors with clinical benefit.

The clinical trial involves a total of **194 participants** diagnosed with **Advanced Renal Cell Carcinoma** with intermediate- or poor-risk factors. 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 inclusion criteria, such as having a histological confirmation of renal carcinoma with a clear cell component, including those with sarcomatoid features, and having advanced or metastatic renal cell carcinoma not amenable to curative surgery or radiation therapy. All participants must have measurable disease by CT or MRI per RECIST 1.1 criteria and must not have received prior systemic therapy for renal cell carcinoma. The trial also considers vulnerable populations, ensuring comprehensive representation. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is a **Phase 3b**, randomized, double-blind study designed to evaluate the efficacy of **nivolumab** combined with **ipilimumab** versus nivolumab monotherapy in patients with previously untreated advanced renal cell carcinoma with intermediate- or poor-risk factors. The trial aims to compare progression-free survival (PFS) and overall response rate (ORR) using RECIST 1.1 criteria among all randomized participants. The study is expected to run from June 24, 2019, to March 11, 2025, with a total duration of approximately 5 years and 9 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological confirmation of renal carcinoma with a clear cell component, measurable disease by CT or MRI, and no prior systemic therapy for renal cell carcinoma. Following randomization, participants will receive either the combination therapy or monotherapy, administered via **intravenous use**. The trial includes regular follow-up visits to monitor treatment response and safety, with assessments conducted by both investigators and a blinded independent central review (BICR).

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants are expected to be involved in the study for up to 104 weeks, depending on their assigned treatment group. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The primary endpoints of the trial are progression-free survival and overall response rate, while secondary endpoints include overall survival, disease control rate, duration of response, and incidence of adverse events.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Ipilimumab** is an experimental medication used in this study. It is provided as a **concentrate for solution for infusion** and is administered via **intravenous use**. The dosing regimen for Ipilimumab involves a maximum daily dose of 1 mg/kg, with a total maximum dose of 4 mg/kg over a treatment period of up to 12 weeks. The active substance in Ipilimumab is a protein-based compound, and it is manufactured by Bristol-Myers Squibb International Corporation. The product is identified by the sponsor product code BMS734016 and is also known by synonyms such as MDX-010, HLX13, and IBI310.

**Nivolumab**, marketed as OPDIVO, is another experimental treatment in the trial. It is available as a **10 mg/mL concentrate for solution for infusion** and is also administered intravenously. The maximum daily dose for Nivolumab is 480 mg, with a total maximum dose of 12,480 mg over a treatment period of up to 104 weeks. The active substance, **nivolumab**, is a protein-based compound, and the product is manufactured by Bristol-Myers Squibb Pharma EEIG. It is identified by the European marketing authorization number EU/1/15/1014/002 and the sponsor product code BMS936558.

In addition to the experimental treatments, the study includes non-experimental treatments such as **Sodium chloride 0.9% solution for infusion** and **5% Dextrose solution for infusion**. These solutions are used as standard-of-care therapies or as placebo comparators. Both solutions are administered intravenously, although specific dosing schedules and administration frequencies are not detailed in the provided data.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to evaluate the efficacy of the combination of Nivolumab and Ipilimumab compared to Nivolumab monotherapy in patients with previously untreated advanced renal cell carcinoma, focusing on progression-free survival (PFS) and overall response rate (ORR) using RECIST 1.1 criteria.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression Free Survival (PFS)** and **Overall Response Rate (ORR)**, both evaluated by Blinded Independent Central Review (BICR) using RECIST 1.1 criteria. These endpoints will measure the time until disease progression or death and the proportion of patients achieving a complete or partial response, respectively.

Secondary endpoints encompass a range of additional efficacy measures, including **Overall Survival (OS)**, **Disease Control Rate (DCR)**, **Duration of Response (DoR)**, and **Time to Objective Response (TTR)**, all assessed by both the Investigator and BICR. The trial will also evaluate PFS and PFS2 as per Investigator assessments, and the incidence of adverse events, including serious adverse events and significant laboratory test changes. Furthermore, the study will explore the relationship between efficacy outcomes and genetic expression profiles (GEP) signatures, as well as programmed cell death protein ligand-1 (PD-L1) expression.

These efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with specific attention to the impact of the combination therapy of nivolumab and ipilimumab compared to nivolumab monotherapy in patients with advanced renal cell carcinoma. The trial is designed to provide comprehensive insights into the therapeutic benefits and safety profile of the treatment regimens under investigation.