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

Официальное название

Prospective, One-arm, Phase II Clinical Study of Smeitinib Hydrosulfate Capsules for the Treatment of Patients With Type I Neurofibromatosis

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Selumetinib
  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)

Первичные конечные точки

• Objective response rate (ORR) [Срок оценки: Within two years of medication]

Вторичные конечные точки (3)

• The scope of the operation can be resected [Срок оценки: Within two years of medication]
• Duration of response (DOR) [Срок оценки: Within two years of medication]
• Progression-free survival (PFS) [Срок оценки: Within two years of medication]

Критерии участия

Критерии включения

• 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;
• Patients who voluntarily participate in the project and sign informed consent.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Идентификаторы

NCT: NCT06620354 · SYSKY-2024-285-02

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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