The Clinical Study of the Treatment of Patients With Type I Neurofibromatosis With Smetinib Hydrosulfate Capsule

This study focused on patients with type I neurofibromatosis undergoing surgical treatment, who currently lack effective drug therapy and have a high recurrence rate after surgical resection. For patients with small solid tumors, limited space, and no invasion of the brain, spine and other important organs, surgical treatment is the main treatment. As a MEK inhibitor, Smetinib bisulfate capsule can induce tumor shrinkage and reduce postoperative recurrence by selectively binding mitogen-activated protein kinase (MEK) 1/2 protein to block the mitogen-activated protein kinase/extracellular signal regulatory kinase signaling pathway that regulates key cell responses. The purpose of this study was to treat patients with type I neurofibromatosis with indications of surgery with the drug smetinib bisulfate after surgical treatment, observe the therapeutic effect of the drug in stages, consolidate the postoperative effect and reduce the recurrence rate. In this study, progression-free survival (PFS) after postoperative drug treatment was used as the main outcome index, and duration of remission (DOR) and objective response rate (ORR) were used as secondary outcome indicators to investigate the efficacy of the use of Smetinib hydrosulfate capsule on tumor control, reduction of recurrence rate and stability of efficacy in patients with type I neurofibromatosis after surgery.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Age ≥18 years old
2. 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
3. Before admission, the head and neck surgeon conducted pathological biopsy of solid tumors, confirmed pathological diagnosis and eliminated malignant peripheral schwannoma (MPNST).
4. There was at least one measurable tumor lesion according to the solid tumor efficacy evaluation criteria RECIST 1.1
5. The tumor did not invade the brain, spine and other important organs, there are indications of surgical resection and surgical treatment
6. The performance of the Eastern Cooperative Oncology Group (ECOG) was 0-1
7. 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).
8. 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.
9. 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.
10. Cardiac function: creatine phosphokinase ≤200U/L, left ventricular ejection fraction (LVEF) ≥50%;
11. Have not participated in other clinical trials within the past 30 days;
12. Patients who voluntarily participate in the project and sign informed consent.

Exclusion Criteria:

1. 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
2. The patient has become malignant peripheral schwannoma (MPNST) or is accompanied by other malignant tumors, heart disease and other serious complications, or has previously received chemotherapy, radiotherapy and other anti-tumor therapy
3. Unable to complete the entire clinical study due to personal, social and economic reasons
4. there is a serious systemic disease in the past and the disease cannot be cured or controlled by medicine at present
5. Pregnant patients

• RESULTLy 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
• RESULTGutmann 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
• RESULTDi 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
• RESULTMiller 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
• RESULTBlakeley 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
• RESULTFriedrich 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
• RESULTPrada 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
• 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.