clinical study on the treatment of type i neurofibromatosis with smeitinib hydrosulfate capsule

Conditions: Neurofibromatosis 1

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.

neurofibromatosis (nf) has been included in the list of rare diseases in many countries, including china, of which 96% is nf1 subtype, nf1 clinical manifestations are diverse, involve multiple systems, can cause respiratory obstruction, spinal cord compression, motor dysfunction and other serious complications. plexiform neurofibroma (pn) occurs in 30-50% of patients with nf1. pn progresses rapidly, is associated with severe physical defects, is highly disabling, and is at risk of malignancy. according to the 2023 edition of the multidisciplinary guidelines for the diagnosis and treatment of type i neurofibromatosis, nf1 patients are more likely than the normal population to develop a variety of benign and malignant tumors, including pnf, cnf, mpnst and opg. attention should be paid to the early identification and monitoring of these tumors. the possibility of mpnst should be highly vigilant for neurofibromas with growth acceleration, pain, and texture hardening. at the same time, systemic evaluation should be performed, and early surgery should be performed as far as possible for patients without signs of distant metastasis, while radiotherapy, chemotherapy and targeted therapy can be selected for patients with distant metastasis. neurofibromatosis type 1 (nf1) is an autosomal dominant disorder in which 50% of patients have familial inherited mutations and 50% have sporadic mutations. nf1 gene encodes neurofibrin, down-regulates the activity of ras-raf pathway, and inhibits cell proliferation. neurofibrin deficiency can lead to overactivation of ras pathway, resulting in uncontrolled cell proliferation in patients with nf1 \[5\]. at present, surgery is the most commonly used and most important treatment for neurofibromatosis, and neurofibroma has the characteristic of growing along the nerve root, so it is difficult to solve all the lesions through surgery. the lesions consist of a wide range of nerve and vascular tissues mixed with normal tissues, and the surgical resection is difficult and bleeding is frequent, and the recurrence after incomplete resection is as high as 50%. as a mek inhibitor, smetinib bisulfate capsule can induce tumor shrinkage 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 cellular responses. to create conditions for disease control, radical surgical resection, reducing postoperative recurrence and reducing complications. based on the targeted therapy of smetinib bisulfate capsule, this study administered medication to enrolled patients. by monitoring the tumor shrinkage effect of patients with solid tumors and evaluating postoperative surgical indications for patients without surgical indications before medication, the effectiveness of smetinib bisulfate capsule in the treatment of nf1 was verified.

Eligibility criteria:
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 invaded the brain, spine and other important organs, no indication of surgical resection 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. 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 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