Efficacy and Safety Evaluation of Naporafenib Combinations in Previously Treated Unresectable or Metastatic BRAFV600/NRAS Mutant Melanoma

The primary objective of this phase II study is to evaluate the **efficacy** of each combination arm in patients with previously treated unresectable or metastatic BRAFV600 or NRAS mutant melanoma. This is assessed based on the Objective Response Rate (ORR) as confirmed by RECIST 1.1, per local assessments. The clinical relevance of this objective lies in determining the potential of these combination therapies to improve treatment outcomes in a patient population with limited options.

Secondary objectives include:

• Characterizing the safety and tolerability of each combination arm through the incidence and severity of adverse events (AEs), including changes in laboratory values, vital signs, cardiac assessment, dose interruptions, reductions, and permanent discontinuations of study treatments.
• Further evaluating the efficacy of each combination arm by duration of response (DOR), progression-free survival (PFS), and disease control rate (DCR) using RECIST v1.1, per local assessment. For expanded treatment combination arms, these parameters will also be evaluated using central assessment.
• Evaluating the overall survival (OS) of each combination arm.
• Characterizing the pharmacokinetics of each combination regimen through serum/plasma concentration and pharmacokinetic parameters.

The clinical trial involves a total of **198 participants** diagnosed with **previously treated unresectable or metastatic BRAFV600 or NRAS mutant melanoma**. The study population includes both male and female subjects aged 12 years and older, with adolescent participants required to have a body weight greater than 40 kg. Participants were selected based on their prior treatment history for unresectable or metastatic melanoma, including systemic therapy with checkpoint inhibitors and, for those with BRAFV600 mutations, targeted therapy with a RAF inhibitor. The trial population is characterized by a history of progressive disease as per RECIST v1.1 criteria following previous treatments. Participants must have a site of disease suitable for repeated biopsies and be willing to undergo these procedures. The study includes a vulnerable population, ensuring comprehensive representation across different demographic groups. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed as a **randomized**, open-label, multi-arm, two-part, phase II study to evaluate the efficacy and safety of multiple combinations of investigational drugs in patients with previously treated unresectable or metastatic **BRAFV600** or **NRAS** mutant melanoma. The primary objective is to assess the efficacy of each combination arm based on the Objective Response Rate (ORR) as confirmed by RECIST 1.1, per local assessments. The trial is expected to run from October 30, 2020, to July 31, 2024, with participants involved for varying durations depending on the treatment arm, with a maximum treatment period of up to 159 days.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body weight, and histological confirmation of melanoma with specific mutations. Following the screening, participants will be randomized into different treatment arms. The trial includes follow-up visits to monitor safety, efficacy, and tolerability, with assessments of adverse events, laboratory values, and vital signs. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

Participants are expected to remain in the study for the duration of their assigned treatment period unless conditions arise that necessitate early termination. Such conditions include the occurrence of severe adverse events, withdrawal of consent, or any other medical reasons deemed significant by the investigator. The trial's design ensures rigorous monitoring and assessment to maintain participant safety and data integrity throughout the study duration.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Ribociclib**, marketed under the product name LEE011, is provided in two forms: a **film-coated tablet** and a **hard capsule**. The maximum daily dose for ribociclib is 400 mg, with a total maximum dose of 216.3 g over a treatment period of 103 days. The administration route is oral, and the medication is of chemical origin, developed by Novartis Pharma AG.

**Trametinib dimethyl sulfoxide**, known as TMT212, is administered as a **film-coated tablet**. The maximum daily dose is 1 mg, with a total maximum dose of 1113 mg over a treatment period of 159 days. This medication is also administered orally and is chemically derived, produced by Novartis Pharma AG.

**Naporafenib**, under the product name LXH254, is available in multiple forms: **film-coated tablet** and **tablet**. The maximum daily dose is 800 mg, with a total maximum dose of 795.2 g over a treatment period of 142 days. The administration is oral, and the substance is of chemical origin, manufactured by Novartis Pharma AG.

**Rineterkib**, marketed as LTT462, is provided in a **hard capsule** form. The maximum daily dose is 200 mg, with a total maximum dose of 155.4 g over a treatment period of 111 days. This medication is administered orally and is chemically derived, produced by Novartis Pharma AG.

All experimental medications in this trial are administered orally, and participant compliance is monitored throughout the study. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Each medication is developed by Novartis Pharma AG and is of chemical origin, ensuring consistency in the trial's pharmaceutical approach.

The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, as confirmed by RECIST 1.1 criteria, based on local assessments. This endpoint will evaluate the proportion of patients who achieve a complete or partial response to the treatment. Secondary efficacy endpoints include Duration of Response (DoR), Progression-Free Survival (PFS), Disease Control Rate (DCR), and Overall Survival (OS), all assessed using RECIST v1.1 criteria. These parameters will be measured both locally and centrally for all participants in the combination arms that proceed to expansion. Additionally, serum/plasma concentration and pharmacokinetic parameters of each combination regimen will be evaluated to further understand the treatment's efficacy.