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

NCT06763315 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: SEL20241219
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

Plexiform Neurofibromas (PN)

Keywords

Neurofibromatosis type 1; Plexiform neurofibromas; Selumetinib; Low-dose

Outcome Measures

Primary Outcomes (1)

• 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%).

  Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).

Secondary Outcomes (8)

• Frequency of adverse events

  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

  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 intensity

  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

  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)

  Once every 3 cycles for the first 12 cycles, once every 6 cycles for the next 12 cycles (each cycle is 28 days).

Study Arms (2)

Regular dose of selumetinib

ACTIVE COMPARATOR

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).

Drug: Selumetinib

Low dose of selumetinib

EXPERIMENTAL

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).

Drug: Selumetinib

Interventions

Selumetinib DRUG

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

Also known as: AZD6244, Koselugo

Low dose of selumetinib; Regular dose of selumetinib

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• West China Hospital: lead

Study Sites (1)

West China Hospital of Sichuan University

Chengdu, Sichuan, 610041, China

Location

Related Publications (6)

• 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.

  PMID: 37115514 BACKGROUND

• 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.

  PMID: 38975694 BACKGROUND

• 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.

  PMID: 35467749 BACKGROUND

• 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.

  PMID: 35579709 BACKGROUND

• 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.

  PMID: 32187457 BACKGROUND

• 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.

  PMID: 28029918 BACKGROUND

MeSH Terms

Conditions

Neurofibroma, Plexiform; Neurofibromatosis 1

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Neurofibromatoses; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Yi Ji, MD, PhD

  West China Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yi Ji, MD, PhD

CONTACT

+862885423453; jijiyuanyuan@163.com

Siyuan Chen, MD, PhD

CONTACT

+862885422215; siy_chen@163.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 25, 2024
• First Posted: January 8, 2025
• Study Start: January 1, 2025
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): October 31, 2028
• Last Updated: January 8, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)