Phase 3 Randomized, Double-Blind Study of Cabozantinib, Nivolumab, and Ipilimumab in Untreated Advanced or Metastatic Renal Cell Carcinoma

The primary objective of this study is to evaluate the **efficacy** and **safety** of a combination therapy involving **cabozantinib**, **nivolumab**, and **ipilimumab** compared to the combination of nivolumab and ipilimumab alone in subjects with previously untreated advanced or metastatic **renal cell carcinoma** (RCC) of intermediate or poor risk. This evaluation is clinically relevant as it aims to determine whether the addition of cabozantinib can enhance treatment outcomes in this patient population, potentially offering a more effective therapeutic option for those with advanced RCC.

The clinical trial involves a total of **517 participants** diagnosed with **Metastatic Renal Cell Carcinoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of advanced or metastatic renal cell carcinoma with a clear-cell component, and classified as intermediate- or poor-risk according to the International Metastatic RCC Database Consortium criteria. All participants exhibit a Karnofsky Performance Status of 70% or higher, indicating a requirement for adequate general health status. The trial also considers vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy and safety across diverse demographic groups. Lifestyle factors such as diet and physical activity are not specified, focusing instead on the medical and functional status of the participants.

The clinical trial is a **randomized, double-blind, controlled** Phase 3 study designed to evaluate the efficacy and safety of **cabozantinib** in combination with **nivolumab** and **ipilimumab** versus nivolumab and ipilimumab alone in subjects with previously untreated advanced or metastatic **renal cell carcinoma** of intermediate or poor risk. The trial is expected to run from November 2019 to December 2025, with the primary endpoint being the duration of **progression-free survival** as assessed by a Blinded Independent Radiology Committee, and a secondary endpoint of overall survival duration.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed advanced or metastatic renal cell carcinoma, intermediate- or poor-risk classification, measurable disease, a Karnofsky Performance Status of 70% or higher, and adequate organ and marrow function. Following successful screening, participants will be randomized to receive either the combination therapy or the control therapy. Study visits will include regular follow-up assessments to monitor safety, efficacy, and disease progression, with the end-of-study visit marking the conclusion of the participant's involvement in the trial.

The expected length of participant involvement is determined by the maximum treatment period, which is 24 months for nivolumab, 18 months for cabozantinib, and 10 months for ipilimumab. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **OPDIVO** (nivolumab), a **concentrate for solution for infusion**. This experimental medication is provided at a concentration of 10 mg/mL and is administered via **intravenous use**. The maximum daily dose is 3 mg/kg, with a total maximum dose of 12,960 mg over a treatment period of up to 24 months. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is specifically packaged and labeled for clinical trial use.

**CABOMETYX** (cabozantinib) is another experimental medication used in this study, provided in the form of **film-coated tablets**. Each tablet contains 20 mg of cabozantinib, and the medication is administered **orally**. The maximum daily dose is 40 mg, with a total maximum dose of 21.6 g over a treatment period of up to 18 months. The tablets are manufactured by Ipsen Pharma and are secondary-packaged and labeled for clinical use, with no additional manufacturing performed for the trial.

A **placebo** is also utilized in the study, designed to match the Cabozantinib (XL184) 20 mg tablets. These placebo tablets are used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered.

Additionally, the trial includes the administration of **YERVOY** (ipilimumab), another **concentrate for solution for infusion**. This medication is provided at a concentration of 5 mg/mL and is administered via **intravenous use**. The maximum daily dose is 1 mg/kg, with a total maximum dose of 4 mg/kg over a treatment period of up to 10 months. Like OPDIVO, YERVOY is manufactured by Bristol-Myers Squibb Pharma EEIG and is specifically packaged and labeled for the clinical trial.

The efficacy of the clinical trial will be assessed using specific endpoints to evaluate the treatment's impact on subjects with advanced or metastatic renal cell carcinoma. The primary endpoint for efficacy assessment is the duration of **Progression-Free Survival (PFS)**, which will be measured according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). This evaluation will be conducted by a Blinded Independent Radiology Committee (BIRC) to ensure objectivity and accuracy in the assessment of tumor progression.

Secondary efficacy endpoints include the duration of **Overall Survival (OS)**, providing additional insights into the treatment's long-term benefits. The collection and analysis of these endpoints will be systematically scheduled throughout the trial duration, with specific timepoints aligned with the study protocol. The trial is designed to compare the efficacy of cabozantinib in combination with nivolumab and ipilimumab versus nivolumab and ipilimumab alone, in subjects who have not received prior treatment for their condition. The study's objective is to determine the potential improvement in survival outcomes and disease progression control in this patient population.