Phase 3 Study of Naporafenib and Trametinib Versus Physician's Choice in NRAS Mutant Cutaneous Melanoma

The primary objective of this study is to determine the optimal dose of **naporafenib** combined with **trametinib** for further investigation in Stage 2. Additionally, Stage 2 aims to compare progression-free survival (PFS) and overall survival (OS) in patients with unresectable or metastatic NRAS mutant cutaneous melanoma who are randomized to receive the combination therapy versus those receiving the physician's choice of therapy, which includes dacarbazine, temozolomide, or trametinib monotherapy. This is clinically relevant as it seeks to establish a more effective treatment regimen for this patient population, potentially improving survival outcomes.

Secondary objectives include: - Stage 1 (Dose Optimization): Evaluating the preliminary clinical activity, safety, tolerability, and pharmacokinetics (PK) of naporafenib and trametinib, both as combination therapy and trametinib as monotherapy. - Stage 2 (Registration-Enabling Portion): Comparing clinical activity measures between the combination therapy and physician's choice, assessing safety and tolerability in each treatment arm, further comparing clinical activity measures, evaluating the PK of the combination therapy, and assessing disease and treatment-related quality of life (QOL) in patients receiving either treatment option.

The clinical trial involves a total of **178 participants** diagnosed with **unresectable or metastatic NRAS mutant cutaneous melanoma**. The study population includes both male and female subjects, aged 18 years and older, who have a confirmed diagnosis of the specified melanoma type. Participants were selected based on their ability to provide written informed consent and meet specific health criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. The trial includes individuals who have previously received an anti-PD-1/L1 based regimen and have documented disease progression. Participants must have at least one measurable lesion according to RECIST v1.1 and be able to swallow oral medication. The trial population is inclusive of vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, phase 3 study aimed at evaluating the efficacy and safety of a combination therapy involving **naporafenib** and **trametinib** compared to the physician's choice of therapy, which includes **dacarbazine**, **temozolomide**, or trametinib monotherapy. The study targets patients with previously treated unresectable or metastatic **NRAS mutant cutaneous melanoma**. The trial is structured in two stages: Stage 1 focuses on dose optimization, while Stage 2 is the registration-enabling portion. The primary objectives include selecting the optimal dose in Stage 1 and comparing progression-free survival (PFS) and overall survival (OS) in Stage 2.

The trial is expected to commence recruitment on September 27, 2024, and conclude by July 30, 2028. Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, documented NRAS mutation, and previous treatment history. Following successful screening, participants will be randomized into treatment groups. Regular follow-up visits will be scheduled to monitor safety, efficacy, and pharmacokinetics, with assessments including laboratory tests, vital signs, and cardiac evaluations. The end-of-study visit will mark the completion of the participant's involvement, which may last up to 28 days, depending on the treatment arm and response.

Participants may be withdrawn from the study early due to adverse events, lack of efficacy, or withdrawal of consent. The trial will adhere to International Council for Harmonization (ICH) guidelines and Good Clinical Practice (GCP) standards, ensuring the integrity and reliability of the data collected. The study's endpoints will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, with a focus on objective response rate (ORR), disease control rate (DCR), and duration of response (DOR). The trial's design and methodology aim to provide robust data to support the potential registration of the combination therapy for this patient population.

The clinical trial involves several treatments, including both experimental and non-experimental medications. **Doxycycline monohydrate** is administered in the form of 100 mg tablets, taken orally. The maximum daily dose is 200 mg, with a treatment period of up to 8 weeks. This medication acts as a tetracycline antibacterial, inhibiting bacterial protein synthesis by binding to ribosomes.

**Trametinib** is provided as 0.5 mg film-coated tablets, also administered orally. The maximum daily dose is 2 mg, with a treatment period of up to 28 days. Trametinib functions as a reversible and highly selective allosteric inhibitor of MEK1 and MEK2.

**Dacarbazine** is available in various formulations, including 500 mg, 200 mg, and 1000 mg powders for solution for infusion, administered intravenously. The maximum daily dose is 1000 mg/m², with a treatment period of up to 21 days. Dacarbazine is a chemotherapy medication and alkylating agent.

**Naporafenib** is administered in tablet form, available in 50 mg, 75 mg, 100 mg, and 200 mg dosages, taken orally. The maximum daily dose is 800 mg, with a treatment period of up to 28 days. Naporafenib acts as an adenosine triphosphate (ATP)-competitive inhibitor of the CRAF and BRAF protein kinase.

**Temozolomide** is provided as hard capsules in 20 mg and 100 mg dosages, administered orally. The maximum daily dose is 200 mg/m², with a treatment period of up to 28 days. Temozolomide is a chemotherapy medication and alkylating agent.

**Hydrocortisone** is available as a 1% w/w cream for cutaneous use. The maximum daily dose is 28 grams, with a treatment period of up to 8 weeks. Hydrocortisone functions as an anti-inflammatory steroid.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial includes a dose optimization lead-in to determine the optimal dose of naporafenib in combination with trametinib, followed by a comparison of progression-free survival and overall survival in patients with NRAS mutant cutaneous melanoma.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Stage 2 of the trial include **Progression-Free Survival (PFS)** using RECIST v1.1 as evaluated by a blinded independent central review (BICR) and Overall Survival (OS). Secondary endpoints for Stage 2 involve the Objective Response Rate (ORR) and Duration of Response (DOR) using RECIST v1.1, also assessed by BICR. Additionally, safety will be evaluated by the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), along with changes from baseline in laboratory values, vital signs, and cardiac assessments such as electrocardiogram (ECG) and echocardiogram (ECHO)/multigated acquisition (MUGA). Tolerability will be measured by AEs leading to dose interruptions, reductions, and permanent discontinuation of study drugs.

In Stage 1, the trial will focus on dose optimization, analyzing the totality of safety, pharmacokinetics (PK), and preliminary efficacy data, including exposure-response relationships for tolerability, safety, and efficacy. Plasma concentrations of naporafenib and trametinib as combination therapy, and trametinib as monotherapy, will be obtained via sparse sampling for population PK modeling. The trial will also assess changes from baseline in EORTC QLQ-C30 subscales and PRO CTCAE® symptoms, with specific endpoints of interest selected based on data from Stage 1 and prespecified before initiating Stage 2. The efficacy assessments will be conducted at various timepoints throughout the trial to ensure comprehensive data collection and analysis.