Dose Optimization of Nivolumab in Patients with Melanoma or Renal Cell Carcinoma Exhibiting Complete, Partial, or Stable Response

The primary objective of the study is to demonstrate that an adequate steady-state level of **nivolumab** is achieved. This is assessed by showing that the mean trough level measured after three reduced doses of nivolumab 240 mg administered every four weeks is not lower than the mean trough level four weeks after the initial treatment dose of 6 mg/kg or 480 mg. This objective is clinically relevant as it aims to optimize dosing regimens for patients with melanoma and renal cell carcinoma, potentially improving therapeutic outcomes and minimizing adverse effects.

Secondary objectives include:

• Exploring PD1 receptor occupancy in PBMCs.
• Assessing the safety of reduced nivolumab doses.
• Evaluating the efficacy of reduced nivolumab doses.
• Characterizing the pharmacokinetic profile of nivolumab.
• Determining the cost-effectiveness of the treatment regimen.

The clinical trial involves participants diagnosed with **melanoma** or **renal cell carcinoma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have advanced or metastatic forms of the disease and must currently be undergoing treatment with nivolumab in a 6 mg/kg or 480 mg, 4 weekly scheme. Additionally, they must have documented confirmed and ongoing complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1 and have been on treatment for at least 6 months. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the **dose optimization** of **nivolumab** in patients with advanced or metastatic **melanoma** or **renal cell carcinoma** who have achieved a complete, partial, or stable response. The trial employs a **randomized**, **double-blind**, and **controlled** design to ensure the reliability and validity of the results. The primary objective is to demonstrate that an adequate steady-state level of nivolumab is achieved with a reduced dosing regimen of 240 mg every four weeks, compared to the standard initial dose of 6 mg/kg or 480 mg. The trial is expected to conclude by July 2025, with recruitment having commenced in April 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), current treatment with nivolumab, and documented response according to RECIST v1.1. Following the screening, participants will receive nivolumab via **intravenous infusion** and attend follow-up visits to monitor the pharmacokinetic profile, PD-1 receptor occupancy, and any adverse events. The primary endpoint is the difference in mean trough levels of nivolumab after the third reduced dose compared to the initial dose. Secondary endpoints include PD-1 receptor occupancy, adverse events, progression during reduced doses, and cost-effectiveness.

The expected duration of participant involvement is approximately three months, corresponding to the maximum treatment period with the reduced dosing regimen. Conditions that may lead to early termination from the study include the occurrence of grade ≥3 adverse events, disease progression, or withdrawal of consent. The trial aims to provide insights into the efficacy and safety of a reduced dosing schedule of nivolumab, potentially informing future therapeutic strategies for patients with melanoma and renal cell carcinoma.

The clinical trial involves the administration of **nivolumab**, an experimental medication, to optimize its dosage in patients with a complete, partial, or stable response. **Nivolumab** is a monoclonal antibody classified under the ATC code L01FF01. It is administered in the form of an intravenous infusion, with a pharmaceutical form designated as PHF00230MIG. The dosing regimen for this trial involves a maximum daily dose of 240 mg, with a total maximum dose of 720 mg over a treatment period of up to 3 months. The primary objective is to demonstrate that an adequate steady-state level is achieved by comparing the mean trough levels after three reduced doses of 240 mg administered every four weeks to the levels observed four weeks after the initial treatment dose of either 6 mg/kg or 480 mg.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of **nivolumab** to assess its pharmacokinetic profile and optimize its dosing schedule. Participant compliance with the dosing regimen is monitored through regular assessments of trough levels to ensure adherence to the prescribed treatment protocol. The trial does not involve any pediatric formulations, and **nivolumab** is not classified as an orphan drug for this study. The trial aims to provide insights into the optimal dosing strategy for **nivolumab** to maintain therapeutic efficacy while minimizing potential adverse effects.

Efficacy in the clinical trial titled "Nivolumab dose optimization in patients with a complete, partial or stable response (NIVOPTIMIZE-trial)" will be assessed primarily by evaluating the **difference between the mean trough level** of nivolumab 4 weeks after the third dose of 240 mg and the mean trough level 4 weeks after the initial treatment dose (6 mg/kg or 480 mg). This primary endpoint aims to demonstrate that an adequate steady-state level is achieved with the reduced dosing regimen.

Secondary endpoints include the assessment of **PD-1 receptor occupancy** in peripheral blood mononuclear cells (PBMCs) measured 4 weeks after three reduced doses, the incidence of grade ≥3 adverse events during the reduced dosing period, the number of patients experiencing new progressive disease (PD) during the three reduced doses, the pharmacokinetic profile of nivolumab, and the cost-effectiveness of the dosing regimen. These parameters will be measured and analyzed at specified timepoints to provide a comprehensive evaluation of the efficacy and safety of the reduced dosing schedule.