Efficacy and Safety Evaluation of Selumetinib in Adults with Neurofibromatosis Type 1 and Symptomatic, Inoperable Plexiform Neurofibromas

The primary objective of this study is to evaluate the efficacy of **selumetinib** compared to placebo by assessing the confirmed partial and complete response rate (ORR) using volumetric MRI analysis, as determined by independent central review (ICR) according to REiNS criteria, in participants with **Neurofibromatosis Type 1 (NF1)** who have symptomatic, inoperable plexiform neurofibromas (PN). This is clinically relevant as it aims to provide evidence for the potential therapeutic benefit of selumetinib in reducing tumor burden in this patient population.

Secondary objectives include:

• Comparing the effect of selumetinib relative to placebo by assessing chronic target PN pain intensity.
• Evaluating the change in health-related quality of life (HRQoL) from baseline in participants with NF1 who have symptomatic, inoperable PN.
• Demonstrating the effectiveness of selumetinib by assessing the confirmed partial and complete response rate (ORR) using volumetric MRI analysis as determined by ICR (per REiNS criteria) in participants with NF1 who have symptomatic, inoperable PN.
• Assessing the safety and tolerability of selumetinib alone and as compared to placebo.
• Evaluating the pharmacokinetics (PK) of selumetinib.

The clinical trial involves a total of **96 participants** diagnosed with **Neurofibromatosis Type 1 (NF1)** with symptomatic, inoperable **Plexiform Neurofibromas (PN)**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on specific criteria, including the presence of at least one target PN measurable by volumetric MRI analysis and a documented chronic target PN pain score during the screening period. Additionally, participants are required to have stable chronic PN pain medication use at enrollment and adequate organ and marrow function. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, double-blind, placebo-controlled study to evaluate the efficacy and safety of **Selumetinib** in adult participants diagnosed with **Neurofibromatosis Type 1 (NF1)** who have symptomatic, inoperable plexiform neurofibromas (PN). The trial will involve two parallel arms, with participants receiving either Selumetinib or a matching placebo. The primary objective is to assess the objective response rate (ORR) using volumetric MRI analysis as determined by independent central review (ICR) per REiNS criteria. Secondary endpoints include changes in chronic target PN pain intensity, PlexiQoL total score, and various other clinical and quality of life measures.

The trial is expected to commence recruitment on April 11, 2024, and conclude by May 25, 2025. Participants will be involved in the study for a maximum treatment period of 43 weeks. The study will begin with a screening visit to confirm eligibility based on criteria such as age (≥18 years), diagnosis of NF1 with symptomatic, inoperable PN, measurable target PN by volumetric MRI, documented chronic target PN pain, stable chronic PN pain medication use, and adequate organ and marrow function. Following successful screening, participants will be randomized to receive either Selumetinib or placebo.

Study visits will be scheduled at regular intervals to monitor safety, efficacy, and pharmacokinetics. These visits will include assessments such as MRI scans, pain evaluations, and quality of life questionnaires. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator.

The clinical trial involves the administration of **SELUMETINIB**, an investigational medication, in the form of hard capsules. The active substance, **selumetinib**, is a chemical compound identified as selumetinib hyd-sulfate. The medication is administered orally. The dosing regimen is specified in milligrams per square meter (mg/m²), although the exact daily and total dose amounts are not provided. The maximum treatment period for participants is 43 days. **SELUMETINIB** is classified under antineoplastic agents and is designated as an orphan drug with the designation number EU/3/18/2050. Participants' compliance with the dosing schedule is monitored throughout the study.

The study also includes a **placebo** designed to match the **Selumetinib** capsules, available in 10 mg and 25 mg dosages. The placebo is administered in the same pharmaceutical form and route as the experimental medication, ensuring blinding in the double-blind, placebo-controlled trial design. The placebo serves as a comparator to evaluate the efficacy and safety of **SELUMETINIB** in adult participants with Neurofibromatosis Type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas. The trial's primary objective is to assess the confirmed partial and complete response rate using volumetric MRI analysis, as determined by independent central review (ICR) per REiNS criteria.

The efficacy of **Selumetinib** in the clinical trial will be assessed primarily through the Objective Response Rate (ORR) using volumetric MRI analysis, as determined by Independent Central Review (ICR) per REiNS criteria. This primary endpoint focuses on evaluating the confirmed partial and complete response rate in participants with Neurofibromatosis Type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). Secondary endpoints include changes from baseline in chronic target PN pain intensity, PlexiQoL total score, duration of response, progression-free survival, time to progression, time to response, and best percentage change from baseline in target PN volume. Additional assessments will cover pain palliation, pain medication use, pain interference, physical functioning, health-related quality of life patient-reported outcomes, and health status. Safety and tolerability, as well as plasma concentrations and pharmacokinetic parameters of selumetinib and N-desmethyl selumetinib, will also be evaluated.