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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
50
Use of the internationally recommended standard dose and low dose of the same drug
West China Hospital of Sichuan University
Chengdu, Sichuan, China
The change in tumor volume of plexiform neurofibromas
Treatment response was measured by volumetric magnetic resonance imaging (MRI) analysis performed at the start of treatment and after 3, 6, 9, 12, 18, and 24 cycles of treatment and independently assessed by 2 radiologists. Changes in PN size were categorized as further growth (increase of ≥20%), no change (\<20% increase and \<20% decrease), partial involution (decrease of ≥20% and \<75%), nearly complete involution (decrease of ≥75% and \<100%), or complete involution (100%).
Time frame: Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).
Frequency of adverse events
Frequency of adverse events (e.g. gastrointestinal disorders, eye disorders, skin disorders, paronychia, abnormal left ventricular ejection fraction, abnormal myocardial marker, abnormal liver function etc.) collected regularly during follow-up by the investigators and reported by the parents. All adverse events were collected and graded according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). The causality of the adverse event was determined by the multidisciplinary staff and was classified as definitively not related, probably not related, possibly related, probably related, or definitively related. Any dose reductions, interruptions, or cessations enacted at the discretion of the investigators were recorded.
Time frame: Once per cycle in the first 3 cycles, once every 3 cycles in the 4th to 12th cycles, and once every 6 cycles in the last 12 cycles (each cycle is 28 days).
Quality of life (QOL) in patients and their families
The Pediatric Quality of Life Inventory (PedsQLTM) 4.0 was used. This genetic core scale is a multidimensional child self-report and parent proxy report measure that assesses health-related quality of life (QOL) in children, adolescents, and young adults aged 2 to 25 years. The PedsQL contains 23 global core measures of QOL, including subscales assessing four domains (physical, emotional, social, and school functioning).
Time frame: Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).
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The change of pain intensity
The Numerical Rating Scale-11 (NRS-11) was used. This scale is a self-report measure that assesses pain intensity on an 11-point numeric scale. It consists of a horizontal line with 0 on the right end, representing "no pain," and 10 on the left end, representing "the worst pain you can imagine." Children aged 8 to 18 years were asked to circle a number from 0 to 10 that best described their worst pain in the past week, including: 1) self-selected most important tumor pain, 2) physician-selected target tumor pain, 3) overall tumor pain, and 4) other types of pain.
Time frame: Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).
The change of pain interference
The Pain Interference Index (PII) is a six-item measure that assesses the extent to which pain has interfered with daily activities over the past week, including concentration, spending time with friends, leisure and physical activities, mood, and sleep. The scale was slightly adapted after translation into English, and a parallel parent version was developed and validated in parents of children with chronic pain. In this study, children aged 8 to 18 years completed the self-report PII, and parents of children aged 5 to 18 years completed the parent-report PII. The total PII score is the average of all six items.
Time frame: Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).
The change of physical functioning (mobility and upper extremity)
The Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function Mobility and Upper Extremity 8-item short forms were used. This short form is used to assess the ability of a person to perform a variety of physical functions over the past 7 days, ranging from motor movements (e.g., standing up from the floor) to activities including self-care skills and vigorous exercise. Children aged 8-18 years completed the Pediatric Self-Report Short Form, and parents of children aged 5-18 years completed the parallel Parent Report Form. These PROMIS Physical Functioning Short Forms demonstrated good psychometric properties, including good reliability and construct validity in adolescents with a variety of medical conditions.
Time frame: Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).
The change of neurocognitive abilities-attention and memory
The Continuous Performance Test (CPT) was used. It assesses the subject's attention, response control, and sustained attention ability by presenting continuous visual or auditory stimuli and requiring the subject to respond according to specific rules. The test content usually includes quickly identifying specific stimuli and responding while ignoring other distracting stimuli. Evaluation indicators include reaction time, accuracy of correct responses, frequency of impulsive responses, and the individual's ability to maintain attention during the task, helping to identify attention deficits or response control problems.
Time frame: Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles(each cycle is 28 days).
The change of neurocognitive abilities-language ability
Peabody Picture Vocabulary Test (PPVT) was used. It is a standardized tool for assessing an individual's vocabulary comprehension ability. It presents a set of pictures and verbal words and asks the subject to choose the picture that best matches the meaning of the word. The test covers words of varying difficulty and assesses an individual's auditory comprehension of words. The main evaluation indicators include language comprehension level, vocabulary, and cognitive ability, which help detect language development, language disorders, and intelligence level.
Time frame: Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).
The change of neurocognitive abilities-executive function
The Stroop test was used. It assesses an individual's inhibitory control and selective attention. It consists of two tasks: one is to ask the subject to report the font color of a word while ignoring the meaning of the word (color word task), and the other is to simply report the font color (simple color task). The test evaluates an individual's cognitive inhibition ability in conflict situations by comparing the performance of these two tasks. The main evaluation indicators include reaction time, task accuracy, and conflict inhibition ability.
Time frame: Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).