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

NCT ID: NCT06763315

Last Updated: 2025-01-08

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-01
• Study Completion Date: 2028-10-31

Brief Summary

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.

Detailed Description

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.

Conditions

Plexiform Neurofibromas (PN)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Regular dose of selumetinib

The total daily dose is 25 mg/m², twice a day, once every 12 hours, and the treatment is continued and followed up for 24 cycles (28 days as one cycle).

Group Type: ACTIVE_COMPARATOR

Selumetinib

Intervention Type: DRUG

Use of the internationally recommended standard dose and low dose of the same drug

Low dose of selumetinib

The total daily dose is 20 mg/m², twice a day, once every 12 hours, and the treatment is continued and followed up for 24 cycles (28 days as one cycle).

Group Type: EXPERIMENTAL

Selumetinib

Intervention Type: DRUG

Use of the internationally recommended standard dose and low dose of the same drug

Interventions

Selumetinib

Use of the internationally recommended standard dose and low dose of the same drug

Intervention Type: DRUG

Other Intervention Names

AZD6244; Koselugo

Eligibility Criteria

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.

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

West China Hospital

OTHER

Sponsor Role: lead

Responsible Party

Yi Ji

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yi Ji, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

West China Hospital

Locations

West China Hospital of Sichuan University

Chengdu, Sichuan, China

Countries

China

Central Contacts

Yi Ji, MD, PhD

Role: CONTACT

jijiyuanyuan@163.com

+862885423453

Siyuan Chen, MD, PhD

Role: CONTACT

siy_chen@163.com

+862885422215

Facility Contacts

Yi Ji, MD, PhD

Role: primary

jijiyuanyuan@163.com

+862885423453

Siyuan Chen, MD, PhD

Role: backup

siy_chen@163.com

Zixin Zhang, MD, PhD

Role: backup

Min Yang, MD, PhD

Role: backup

References

Gross AM, Dombi E, Wolters PL, Baldwin A, Dufek A, Herrera K, Martin S, Derdak J, Heisey KS, Whitcomb PM, Steinberg SM, Venzon DJ, Fisher MJ, Kim A, Bornhorst M, Weiss BD, Blakeley JO, Smith MA, Widemann BC. Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas. Neuro Oncol. 2023 Oct 3;25(10):1883-1894. doi: 10.1093/neuonc/noad086.

Reference Type: BACKGROUND

PMID: 37115514 (View on PubMed)

Kim H, Yoon HM, Kim EK, Ra YS, Kim HW, Yum MS, Kim MJ, Baek JS, Sung YS, Lee SM, Lim HS, Lee BJ, Lim HT, Kim D, Yoon J, Bae H, Hwang S, Choi YH, Kim KA, Choi IH, Lee SW, Park SJ, Lee BH. Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma. Neuro Oncol. 2024 Dec 5;26(12):2352-2363. doi: 10.1093/neuonc/noae121.

Reference Type: BACKGROUND

PMID: 38975694 (View on PubMed)

Gross AM, Glassberg B, Wolters PL, Dombi E, Baldwin A, Fisher MJ, Kim A, Bornhorst M, Weiss BD, Blakeley JO, Whitcomb P, Paul SM, Steinberg SM, Venzon DJ, Martin S, Carbonell A, Heisey K, Therrien J, Kapustina O, Dufek A, Derdak J, Smith MA, Widemann BC. Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity. Neuro Oncol. 2022 Nov 2;24(11):1978-1988. doi: 10.1093/neuonc/noac109.

Reference Type: BACKGROUND

PMID: 35467749 (View on PubMed)

Yang X, Yoo HK, Amin S, Cheng WY, Sundaresan S, Zhang L, Duh MS. Clinical and humanistic burden among pediatric patients with neurofibromatosis type 1 and plexiform neurofibroma in the USA. Childs Nerv Syst. 2022 Aug;38(8):1513-1522. doi: 10.1007/s00381-022-05513-8. Epub 2022 May 17.

Reference Type: BACKGROUND

PMID: 35579709 (View on PubMed)

Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18.

Reference Type: BACKGROUND

PMID: 32187457 (View on PubMed)

Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943.

Reference Type: BACKGROUND

PMID: 28029918 (View on PubMed)

Other Identifiers

SEL20241219

Identifier Type: -

Identifier Source: org_study_id