Phase 3 Multicenter Study Comparing Tivozanib Plus Nivolumab Versus Tivozanib Monotherapy in Renal Cell Carcinoma Post-Immune Checkpoint Inhibitor Therapy

The primary objective of this study is to compare the **progression-free survival** (PFS) of tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with **renal cell carcinoma** (RCC) who have progressed following one or two lines of therapy, including an immune checkpoint inhibitor. This is assessed by a blinded independent radiological review. The clinical relevance of this objective lies in determining the efficacy of the combination therapy in extending the time patients live without disease progression, which is crucial for improving treatment strategies in RCC.

Secondary objectives include:

• Comparing the overall survival (OS) of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib alone.
• Assessing PFS as evaluated by the investigator.
• Comparing the overall response rate (ORR) and duration of response (DoR) of subjects treated with the combination therapy versus monotherapy, as assessed by blinded independent radiological review and investigator.
• Evaluating the safety and tolerability of tivozanib in combination with nivolumab compared to tivozanib monotherapy.

The clinical trial involves a total of **157 participants** diagnosed with **renal cell carcinoma**. The study population includes both male and female subjects, aged 18 years and older, who have experienced disease progression following one or two lines of therapy that included an immune checkpoint inhibitor. Participants are required to have a life expectancy of at least three months and must have recovered from prior therapy-related adverse events to a grade of 1 or baseline. The trial does not include vulnerable populations. Subjects must have histologically or cytologically confirmed renal cell carcinoma with a clear cell component and measurable disease as per RECIST criteria Version 1.1. An Eastern Cooperative Oncology Group performance status of 0 or 1 is required. All participants are expected to adhere to protocol-defined contraceptive measures. The selection process ensures that participants have undergone radiographic disease progression during or after at least six weeks of treatment with an immune checkpoint inhibitor for locally advanced or metastatic renal cell carcinoma with a clear cell component, either in first- or second-line treatment.

The clinical trial is designed as a **randomized**, controlled, multicenter, open-label study to evaluate the efficacy of **tivozanib** in combination with **nivolumab** compared to tivozanib monotherapy in subjects with **renal cell carcinoma**. The primary objective is to assess progression-free survival (PFS) in patients who have progressed following one or two lines of therapy, including an immune checkpoint inhibitor. The trial is expected to last until July 31, 2025, with recruitment having commenced on November 1, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease progression, and performance status. The trial will include follow-up visits to monitor treatment response and safety, with assessments conducted according to RECIST criteria Version 1.1. The end-of-study visit will conclude the participant's involvement, evaluating overall survival and objective response rate.

The expected duration of participant involvement is up to 52 weeks for those receiving tivozanib and up to 24 weeks for those receiving nivolumab. Conditions that may lead to early termination from the study include significant adverse events or disease progression as determined by the investigator. The trial will ensure rigorous monitoring of safety and efficacy endpoints, with a blinded independent radiological review assessing PFS.

The clinical trial involves the administration of **TIVOZANIB**, a chemical compound used as an experimental medication. Tivozanib is provided in the form of a hard capsule and is administered orally. The maximum daily dose of tivozanib is 1.34 mg, with a total maximum dose of 675.36 mg over a treatment period of up to 52 weeks. An alternative dosing regimen includes a maximum daily dose of 0.89 mg, with a total maximum dose of 448.56 mg over the same treatment period. The administration schedule is designed to ensure optimal therapeutic outcomes while monitoring participant compliance through regular assessments.

In addition to tivozanib, the study also includes the administration of **NIVOLUMAB**, marketed under the name OPDIVO. Nivolumab is a biological product of protein origin, specifically a concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 480 mg and a total maximum dose of 11,520 mg over a treatment period of up to 24 weeks. The infusion schedule is carefully managed to maintain therapeutic levels and monitor participant adherence to the treatment protocol.

The trial compares the efficacy of tivozanib in combination with nivolumab against tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy, including an immune checkpoint inhibitor. The study is designed to assess progression-free survival, with all treatments administered under controlled conditions to ensure participant safety and data integrity.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**. This parameter will compare the PFS of subjects receiving tivozanib in combination with nivolumab to those receiving tivozanib monotherapy. PFS is defined as the time from randomization to the first documentation of objective tumor progression, as determined by radiological assessment according to RECIST criteria, or death from any cause, whichever occurs first. This assessment will be conducted by a blinded independent radiological review.

Secondary efficacy endpoints include **overall survival (OS)**, which measures the time from randomization to death from any cause, and **objective response rate (ORR)**, defined as the proportion of subjects achieving a confirmed complete or partial response according to RECIST criteria. Additionally, the **duration of response (DoR)** will be evaluated, defined as the time from the first documentation of objective tumor response to the first documentation of tumor progression or death. Safety and tolerability will also be assessed by monitoring the number of subjects experiencing serious and non-serious adverse events.