Evaluation of Diclofenac in Combination with PD-1 Inhibitors Nivolumab or Pembrolizumab in Metastatic Melanoma with Stable Disease Response

The primary objective of this study is to evaluate the **efficacy** of adding **diclofenac** to an approved, ongoing **PD-1 inhibitor therapy** in patients with **metastatic melanoma** who have achieved stable disease as their best response. This is clinically relevant as it explores the potential for diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), to enhance the therapeutic effects of PD-1 inhibitors, which are pivotal in the management of metastatic melanoma. The study aims to determine whether this combination can improve patient outcomes by potentially overcoming the limitations of stable disease status in this patient population.

The clinical trial involves participants diagnosed with **metastatic melanoma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. The trial does not include a vulnerable population. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of unresectable metastatic melanoma and ongoing treatment with an approved anti-PD-1 therapy, achieving stable disease as the best response. Those with BRAF-V600 mutations must have previously received targeted therapy. Additionally, participants must have adequate tumor tissue accessible for biopsy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **diclofenac** when added to an approved, ongoing PD-1 inhibitor therapy in patients with **metastatic melanoma** who have achieved stable disease as the best response. This is a single-arm, phase II trial. The study employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to commence on January 1, 2024, and conclude by December 31, 2029, with the primary endpoint being the objective response at week 9, defined as a confirmed best response of either a complete response or a partial response, assessed using diagnostic-quality PET-CT according to RECIST 1.1 criteria.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed, unresectable metastatic melanoma, ongoing treatment with an approved anti-PD-1 therapy, and adequate organ function. Follow-up visits will be scheduled to monitor the participants' response to the treatment and any adverse effects. The end-of-study visit will mark the conclusion of the participant's involvement in the trial, where final assessments will be conducted.

The expected length of participant involvement is up to 63 days, with conditions for early termination including the occurrence of unacceptable adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial will utilize **nivolumab** and **pembrolizumab** administered via intravenous infusion, alongside **diclofenac sodium** and **pantoprazole** in gastro-resistant tablet form, to explore the potential benefits of combining these treatments in the specified patient population.

The clinical trial involves the administration of **Nivolumab**, an experimental medication classified under the ATC code L01FF01. Nivolumab is provided in a pharmaceutical form designated as PHF00230MIG and is administered via **intravenous infusion**. The maximum daily dose is 480 mg, with a total maximum dose of 8640 mg over a treatment period of 24 weeks. This medication is not a paediatric formulation and is not classified as an orphan drug. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Diclofenac Sodium** is used as a non-experimental treatment in the study. It is available in two formulations: Diclo 50 - 1 A Pharma 50 mg gastro-resistant tablets and Diclofenac AL 25 mg gastro-resistant tablets. Both formulations are administered **orally**. The maximum daily dose for Diclofenac Sodium is 150 mg, with a treatment period extending up to 63 days. Diclofenac Sodium is classified as a nonsteroidal anti-inflammatory drug (NSAID) and is not a paediatric formulation or an orphan drug.

**Pantoprazole** is another non-experimental treatment used in the study, provided as Pantoprazol TAD® 20 mg gastro-resistant tablets. This medication is administered **orally** with a maximum daily dose of 80 mg over a treatment period of 63 days. Pantoprazole is classified as a proton pump inhibitor (PPI) and is not a paediatric formulation or an orphan drug.

**Pembrolizumab** is also included in the trial as an experimental medication, classified under the ATC code L01FF02. It is provided in a pharmaceutical form designated as PHF00230MIG and administered via **intravenous infusion**. The maximum daily dose is 400 mg, with a total maximum dose of 7200 mg over a treatment period of 24 weeks. Pembrolizumab is not a paediatric formulation and is not classified as an orphan drug. Compliance with the dosing schedule will be closely monitored.

The efficacy of the clinical trial will be assessed by evaluating the **objective response (OR)** at week 9, specifically at visit 3 (day 64 ± 5 days). The primary endpoint is defined as a confirmed best response of either a complete response (CR) or a partial response (PR). This assessment will be conducted through investigator evaluation using positron emission tomography in combination with computed tomography with contrast agent (diagnostic-quality PET-CT), following the Response Evaluation Criteria in Solid Tumor, version 1.1 (RECIST 1.1). The trial aims to determine the efficacy of adding diclofenac to an ongoing PD-1 inhibitor therapy in patients with metastatic melanoma who have achieved stable disease (SD) as the best response. The trial is a single-arm phase II study, and the primary endpoint will provide insights into the potential benefits of this combination therapy in the specified patient population.