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

Phase 2

Not yet recruiting

• Conditions: Neurofibromatosis 1
• Interventions: Drug: Selumetinib

• Registration Number: NCT06621082
• Lead Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Brief Summary

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.

Detailed Description

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 defects can lead to overactivation of the RAS pathway, resulting in uncontrolled cell proliferation in patients with NF1. 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%. For NF1 in the head and neck, some patients require a second operation one year after surgery, and the proportion of patients with partial resection undergoing a second operation is higher than that of patients with subtotal resection. Five years after surgery, more than 50% of patients needed a second operation.

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 smeitinib bisulfate capsule, this study evaluated the treatment of NF1 patients after surgical treatment, and evaluated the effect of tumor shrinkage after medication by monitoring the effect and duration of solid tumor shrinkage of patients. And the postoperative recurrence time, so as to verify the effectiveness of smeitinib bisulfate capsule in reducing the recurrence rate of patients after NF1.

Study Timeline

• Study First Submitted: 2024-08-20
• Status Verified: 2024-09
• Study First Submitted QC: 2024-09-27
• Last Update Submitted: 2024-09-27
• Study Start: 2024-09-30
• Study First Posted: 2024-10-01
• Last Update Posted: 2024-10-01
• Primary Completion: 2026-11-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 19

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Postoperative drug group	Selumetinib	This study started from the recruitment of subjects, confirmed diagnosis by clinical diagnosis and pathological biopsy, preliminary screening according to inclusion and exclusion criteria, and signing of informed consent. Patients who were evaluated as indications for surgical resection and underwent surgical treatment were treated with Smetinib bisulfate capsules. PFS, ORR, and DOR were evaluated after 6 cycles of administration of Simetinib bisulfate capsules (20-50mg bid) daily for 30 days, as individualized by patient body surface area (BSA).

Primary Outcome Measures

Name	Time	Method
2-year progression-free survival (2-year PFS rate)	Within 2 years from the start of treatment in the trial	Refers to the rate of postoperative patients who are free of tumor progression or death from any cause (whichever occurs first) within 2 years from the start of treatment in the trial.

Secondary Outcome Measures

Name	Time	Method
Duration of remission	Within 2 years from the start of treatment in the trial	Refers to the time from the first evaluation of a tumor as CR or PR to the first evaluation as PD or death from any cause
Objective response rate	Within 2 years from the start of treatment in the trial	The proportion of patients whose tumors shrink by ≥ 20% for a certain period of time, including complete response (CR) and partial response (PR) cases. ORR was defined as the proportion of patients whose tumor size decreased by ≥ 20% in the shortest time.