Low-dose Selumetinib for the Treatment of Plexiform Neurofibromas in Chinese Children

The Efficacy, Safety, and Long-Term Prognosis of Low-Dose Selumetinib in the Treatment of Neurofibromatosis Type 1 Associated Plexiform Neurofibromas in Chinese Children: a Multicenter Randomized Controlled Trial

The goal of this study is to compare the efficacy and safety of low-dose and internationally recommended standard dose of selumetinib in the treatment of plexiform neurofibromas in Chinese children.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that affects multiple organ systems, with an estimated prevalence of approximately 1/3000. Around 50% of NF1 develop plexiform neurofibromas (PN), which can exhibit invasive growth, leading to compression of surrounding tissues. PN can progress rapidly within a short period, resulting in severe deformities and functional impairments that significantly impact the patient's quality of life.

In 2020, selumetinib was approved in the United States for the treatment of symptomatic PN patients aged ≥2 years who were ineligible for surgery, bringing new breakthroughs to this large patient population in China. In recent years, clinical trials have been conducted in many countries and regions to evaluate the efficacy and safety of selumetinib in the treatment of PN. Studies have demonstrated that after one year of treatment, 70% of patients achieved confirmed partial lesion reduction, accompanied by significant improvements in pain symptoms and quality of life. Furthermore, the safety was favorable, with 97.7% of adverse reactions classified as Grade I or II. In China, a single-arm clinical trial involving 16 children also showed that all patients had controlled lesions, of which 63% of children had confirmed partial relief. However, the current dosage for children in China refers to the recommended value of Phase I clinical trials (25 mg/m²) in the United States. There remains a lack of pharmacokinetic and pharmacodynamic data specific to the Chinese population. Since racial differences can influence drug metabolism, the current dosage may exceed the tolerance level for some Chinese children, potentially increasing the risk of serious adverse reactions. Clinically, families frequently report a high incidence of adverse effects such as paronychia, abdominal pain, and rash.

Therefore, conducting a dose optimization study based on the Chinese population and exploring the efficacy and safety of low-dose selumetinib in the treatment of PN in Chinese children is of great significance. These efforts will guide clinical practice, reduce adverse reactions, and enhance treatment outcomes.

Inclusion Criteria:

• Male and females;
• Between 3 and 18 years of age;
• Diagnosis of NF1 as determined by meeting at least 2 of the following 7 criteria: (1) six or more cafe-au-lait macules (greater than or equal to 0.5cm in prepubertal subjects or greater than or equal to1.5 cm in post pubertal subjects); (2) two or more neurofibromas (any type); (3) freckling in axilla or groin; (4) optic glioma; (5) two or more Lisch nodules; (6) a distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex); (7) a first-degree relative with NF1;
• Diagnosis of PN as determined by biopsy and pathological diagnosis;
• Complete resection of PN is not feasible without significant morbidity risk;
• Normal liver, kidney, and heart function;
• Previous treatment, last dose time: colony stimulating factor≥1 week, radiotherapy≥6 weeks, other study drugs>30 days;
• Able to undergo MRI evaluation;
• Consent of parents (or the person with parental authority in families): signed and dated written informed consent.

Exclusion Criteria:

• Patients with contraindications to selumetinib administration (e.g., allergy to selumetinib);
• Unable to swallow the entire selumetinib capsule;
• Ongoing hormone, immunotherapy, or chemotherapy for PN;
• Previously received multiple myelosuppressive chemotherapy regimens;
• Suffering from other severe and/or uncontrolled systemic diseases not related to NF1 (e.g., uncontrolled diabetes, hypertension, severe malnutrition, chronic liver or kidney disease, active gastrointestinal ulcers, etc.);
• Presence of optic nerve glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancers requiring chemotherapy or radiotherapy;
• Presence of severe local or systemic uncontrolled infections;
• Impaired gastrointestinal function or chronic gastrointestinal diseases that may significantly affect the absorption of selumetinib;
• Patients with inadequate liver function: total bilirubin higher than or equal to 1.5 × the upper limit of the normal (ULN) for age and alanine aminotransferase and aspartate aminotransferase higher than or equal to 2.5 × the ULN for age;
• Patients with inadequate renal function: 3-5 years of age maximum serum creatinine (mg/dL) of 0.8; 6-10 years of age maximum serum creatinine (mg/dL) of 1.0; 11-18 years of age maximum serum creatinine (mg/dL) of 1.2;
• Insufficient bone marrow function: absolute neutrophil count lower than 1×109/L;
• Patients with cardiac insufficiency: echocardiogram shows abnormal ejection fraction;
• HIV-infected patients or patients with known immunodeficiency;
• Patients with a history of treatment with selumetinib or other MEK inhibitors;
• Patients who are unable to participate in treatment or follow-up evaluation plans during the study;
• Patients who are unable to give informed consent.