Clinical Study on the Treatment of Type I Neurofibromatosis With Smeitinib Hydrosulfate Capsule

NCT06620354 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: SYSKY-2024-285-02
• Study Type: interventional
• Target: 33
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study focused on patients with type I neurofibromatosis, who currently lack effective drug therapy and have a high recurrence rate after surgical resection. As a MEK inhibitor, Smetinib bisulfate capsule can induce tumor shrinkage by selectively binding mitogen-activated protein kinase (MEK) 1/2 protein, blocking the mitogen-activated protein kinase/extracellular signal regulatory kinase signaling pathway that regulates key cell responses. To create conditions for disease control, radical surgical resection, reducing postoperative recurrence and reducing complications. The purpose of this study was to provide treatment with Smetinib bisulfate for patients with type I neurofibromatosis, observe the therapeutic effect in stages, convert patients without surgical indications into patients with surgical indications, increase the proportion of surgical resection and reduce the recurrence rate. Objective tumor response rate (ORR) after drug treatment was used as the main outcome index in this study. The resectable scope, duration of remission (DOR), progression-free survival (PFS) were used as secondary outcome indicators to investigate the improvement of resectable rate, reduction of resectable scope and postoperative complications, tumor shrinkage effect, and the stability of curative effect of the use of smetinib bisulfate capsule on type I neurofibromatosis.

Conditions

Neurofibromatosis 1

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR)

  Percentage of patients with a partial response confirmed by analysis after 6 cycles of drug therapy. A partial response is defined as a reduction in the target neurofibroma volume of ≥ 20% from baseline. A confirmed partial response was defined as a partial response assessed by successive re-staging examinations at intervals of ≥ 3 months.

  Within two years of medication

Secondary Outcomes (3)

• The scope of the operation can be resected

  Within two years of medication

• Duration of response (DOR)

  Within two years of medication

• Progression-free survival (PFS)

  Within two years of medication

Study Arms (1)

Drug group

EXPERIMENTAL

Patients assessed as having no indication for surgical resection were treated with smetinib bisulfate capsules. Based on individual patient body surface area (BSA), Smetinib bisulfate capsules (20-50mg bid) were taken orally daily for 30 days for 6 cycles to evaluate tumor reduction efficacy, ORR, and resection range.

Drug: Selumetinib

Interventions

Selumetinib DRUG

Patients without indications for surgical excision were evaluated with 6 cycles of daily oral smetinib capsules (20-50mg bid) for 30 days, individually calculated based on patient body surface area (BSA)

Drug group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years old
• According to the National Institutes of Health (NIH) updated diagnostic criteria for NF1 in 2021, 6 or more CALMs: d\>5 mm before puberty or d\>15 mm after puberty; 2 or more neurofibromas of any type or 1 plexiform neurofibroma;
• ③ Freckles in the armpit or groin area;
• ④ optic glioma (OPG);
• ⑤ Two or more Lisch nodules were detected by slit-lamp, or two or more choroidal abnormalities were detected by optical coherence tomography (OCT)/ near-infrared (NIR) imaging;
• ⑥ Characteristic bone lesions, such as sphenoid dysplasia, anterolateral tibial curvature; Pathogenic heterozygote NF1 variant with 50% allele variant fraction in normal tissues (such as white blood cells); NF1 is diagnosed in persons who have no history of parental disease and meet 2 or more clinical characteristics Individuals with a history of parental disease who meet one or more clinical characteristics may be diagnosed with NF1
• Before admission, the head and neck surgeon conducted pathological biopsy of solid tumors, confirmed pathological diagnosis and eliminated malignant peripheral schwannoma (MPNST).
• There was at least one measurable tumor lesion according to the solid tumor efficacy evaluation criteria RECIST 1.1
• The tumor invaded the brain, spine and other important organs, no indication of surgical resection
• The performance of the Eastern Cooperative Oncology Group (ECOG) was 0-1
• Blood routine: white blood cell count (WBC) ≥3.0×109/L; Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelet (PLT) ≥ 100×109/L; Hemoglobin level (HGB) ≥ 9.0 g/dL (7 days without corresponding supportive treatment, such as blood transfusion and increased white blood cells).
• Liver function: the patient's aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were less than 2.5 times the upper limit of reference value (ULN); Albumin (ALB) ≥ 30 g/L.
• Renal function: serum creatinine ≤1.5 times ULN or creatinine clearance (CrCl) ≥ 50mL/min (using Cockcroft/Gault formula); Urinary protein (UPRO) \< (++), or 24-hour urinary protein volume \< 1.0 g.
• Cardiac function: creatine phosphokinase ≤200U/L, left ventricular ejection fraction (LVEF) ≥50%;
• Have not participated in other clinical trials within the past 30 days;

You may not qualify if:

• The patient had abnormal blood indexes and abnormal liver, kidney and heart function, and could not tolerate the clinical study process after multidisciplinary consultation and evaluation
• Patients have malignant peripheral schwannoma (MPNST) or other malignant tumors, heart disease and other serious complications, or have previously undergone anti-tumor therapy such as surgery, chemotherapy, radiotherapy
• Unable to complete the entire clinical study due to personal, social and economic reasons
• there is a serious systemic disease in the past and the disease cannot be cured or controlled by medicine at present
• Pregnant patients

Sponsors & Collaborators

• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University: lead

Related Publications (15)

• Ly KI, Blakeley JO. The Diagnosis and Management of Neurofibromatosis Type 1. Med Clin North Am. 2019 Nov;103(6):1035-1054. doi: 10.1016/j.mcna.2019.07.004.

  PMID: 31582003 RESULT

• Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017 Feb 23;3:17004. doi: 10.1038/nrdp.2017.4.

  PMID: 28230061 RESULT

• Di Rocc C, Samii A, Tamburrini G, Massimi L, Giordano M. Sphenoid dysplasia in neurofibromatosis type 1: a new technique for repair. Childs Nerv Syst. 2017 Jun;33(6):983-986. doi: 10.1007/s00381-017-3408-z. Epub 2017 Apr 13.

  PMID: 28409229 RESULT

• Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR; COUNCIL ON GENETICS; AMERICAN COLLEGE OF MEDICAL GENETICS AND GENOMICS. Health Supervision for Children With Neurofibromatosis Type 1. Pediatrics. 2019 May;143(5):e20190660. doi: 10.1542/peds.2019-0660.

  PMID: 31010905 RESULT

• Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol. 2016 May;18(5):624-38. doi: 10.1093/neuonc/nov200. Epub 2016 Feb 6.

  PMID: 26851632 RESULT

• Friedrich RE, Schmelzle R, Hartmann M, Funsterer C, Mautner VF. Resection of small plexiform neurofibromas in neurofibromatosis type 1 children. World J Surg Oncol. 2005 Jan 31;3(1):6. doi: 10.1186/1477-7819-3-6.

  PMID: 15683544 RESULT

• Prada CE, Rangwala FA, Martin LJ, Lovell AM, Saal HM, Schorry EK, Hopkin RJ. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J Pediatr. 2012 Mar;160(3):461-7. doi: 10.1016/j.jpeds.2011.08.051. Epub 2011 Oct 11.

  PMID: 21996156 RESULT

• Gross AM, Singh G, Akshintala S, Baldwin A, Dombi E, Ukwuani S, Goodwin A, Liewehr DJ, Steinberg SM, Widemann BC. Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. Neuro Oncol. 2018 Nov 12;20(12):1643-1651. doi: 10.1093/neuonc/noy067.

  PMID: 29718344 RESULT

• Martin S, Wolters P, Baldwin A, Gillespie A, Dombi E, Walker K, Widemann B. Social-emotional functioning of children and adolescents with neurofibromatosis type 1 and plexiform neurofibromas: relationships with cognitive, disease, and environmental variables. J Pediatr Psychol. 2012 Aug;37(7):713-24. doi: 10.1093/jpepsy/jsr124. Epub 2012 Feb 21.

  PMID: 22353803 RESULT

• Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007 Feb;44(2):81-8. doi: 10.1136/jmg.2006.045906. Epub 2006 Nov 14.

  PMID: 17105749 RESULT

• Anderson MK, Johnson M, Thornburg L, Halford Z. A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. Ann Pharmacother. 2022 Jun;56(6):716-726. doi: 10.1177/10600280211046298. Epub 2021 Sep 18.

  PMID: 34541874 RESULT

• Harder A. MEK inhibitors - novel targeted therapies of neurofibromatosis associated benign and malignant lesions. Biomark Res. 2021 Apr 16;9(1):26. doi: 10.1186/s40364-021-00281-0.

  PMID: 33863389 RESULT

• Campagne O, Yeo KK, Fangusaro J, Stewart CF. Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib. Clin Pharmacokinet. 2021 Mar;60(3):283-303. doi: 10.1007/s40262-020-00967-y. Epub 2020 Dec 23.

  PMID: 33354735 RESULT

• 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 RESULT

• 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 RESULT

MeSH Terms

Conditions

Neurofibromatosis 1

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

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

Study Officials

• Zhiquan Huang, doctoral

  Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zhiquan Huang, doctoral

CONTACT

13826142898; hzhquan@mail.sysu.edu.cn

Zixian Huang, doctoral

CONTACT

15018754725; 258001917@qq.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 20, 2024
• First Posted: October 1, 2024
• Study Start: September 30, 2024
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: October 1, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share