An Open-Label, Single-Arm Exploratory Clinical Study of Everolimus for the Treatment of Vascular Malformations

An Open-Label, Single-Arm Exploratory Clinical Study of Everolimus for the Treatment of Vascular Malformations

This study is a single-arm exploratory trial conducted by Xuanwu Hospital, Capital Medical University, aiming to evaluate the efficacy and safety of everolimus monotherapy in adult patients with vascular malformations.

This study is a single-arm exploratory trial designed to evaluate the efficacy and safety of everolimus monotherapy in adult patients with vascular malformations.

A total of 10 participants aged 18 to 65 years with a confirmed diagnosis of vascular malformation will be enrolled. Eligible patients must be deemed by the investigator to be unsuitable for effective surgical treatment. After screening, qualified participants will receive oral everolimus once daily in continuous cycles of 28 days. The daily dosage of everolimus for adult patients will be 10 mg. Treatment will continue until disease progression, intolerable toxicity, lack of clinical benefit as determined by the investigator, study termination, or any other pre-defined discontinuation criteria-whichever occurs first.

The primary objective of this study is to assess the therapeutic efficacy of everolimus in patients with vascular malformations, primarily through evaluation of lesion volume using MRI sequences. All participants will undergo MRI-based target lesion volume analysis and assessments of microbleeding, iron deposition, and hemorrhage risk during the screening period, at the end of treatment cycles 3, 6, and 12, every 6 cycles thereafter, and at the end-of-treatment (EOT) visit. Clinical signs, symptom scores, and quality-of-life improvements will also be evaluated. The acceptable window for these assessments is ±7 days. If a participant has not undergone efficacy evaluation within 3 months, a final assessment should be conducted at the EOT visit.

Inclusion Criteria

• Patients aged ≥18 and ≤65 years;
• No gender restrictions;
• Diagnosed with vascular malformation by MRI;
• No major surgery within the past 3 months;
• Able to swallow and retain oral medication, with no significant gastrointestinal abnormalities that may affect drug absorption, such as malabsorption syndrome, intestinal obstruction, or extensive gastrointestinal resection;
• Able to provide peripheral blood samples for biomarker testing at a central laboratory;
• Patients must have adequate organ and bone marrow function, and must not have received blood transfusions or any supportive treatments (e.g., cytokines or erythropoietin) to increase white blood cells, platelets, or hemoglobin levels within 7 days before screening tests:Absolute neutrophil count ≥1.0×10⁹/L;Hemoglobin ≥90 g/L; Platelets ≥100×10⁹/L;Total bilirubin ≤1.5× upper limit of normal (ULN), or ≤3.0× ULN for patients with Gilbert's syndrome;AST and ALT ≤2.5× ULN;Albumin ≥3 g/dL; Serum creatinine <1.5× ULN or creatinine clearance ≥50 mL/min;Urine protein <2+; if ≥2+, then 24-hour urine protein must be ≤1 g;Coagulation: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤1.5× ULN.
• Patients must voluntarily sign the written informed consent form and be able to complete follow-up;
• For patients of childbearing potential: they must agree to use highly effective contraceptive methods, such as combined hormonal contraception, progestogen-only hormonal contraception associated with ovulation inhibition, intrauterine devices (IUDs), intrauterine hormonal systems (IUS), bilateral tubal occlusion, or partner vasectomy, or to practice sexual abstinence during the treatment period and for at least 90 days after the last dose. Male patients must agree to refrain from sperm donation for at least 90 days after the last dose.

Exclusion Criteria:

• Diagnosed with Hereditary Hemorrhagic Telangiectasia (HHT), Arteriovenous Malformation (AVM), or PTEN Hamartoma Tumor Syndrome (PHTS);
• Patients who have previously received any of the following treatments after birth: participation in other interventional clinical trials targeting cerebral cavernous malformations (CM);
• Presence of malignant tumors currently or within the past three years, except for curatively treated non-melanoma skin basal cell carcinoma, ductal carcinoma in situ of the breast, or cervical carcinoma in situ;
• Unable to undergo MRI scans and/or have contraindications for MRI (e.g., interference from prosthetics, orthodontic devices, etc., affecting target lesion volume analysis on MRI);
• Modified Rankin Scale (mRS) score of 5, respiratory failure, or currently experiencing severe bleeding requiring life-support treatment;
• Severe renal failure (e.g., creatinine clearance \[CrCl] < 30 mL/min, or significantly elevated serum creatinine not correctable by other means), recent history (within past 3 months) of renal failure or end-stage renal disease without effective treatment, or currently undergoing dialysis;
• Severe hepatic failure, including but not limited to: Child-Pugh Class C or higher, recent (within 3 months) uncontrolled symptoms related to hepatic failure such as ascites, jaundice, coagulopathy, or hepatic encephalopathy, or patients requiring liver transplantation;
• Currently using other immunosuppressants or patients with immunodeficiency;
• Patients requiring use of medications that interfere with or inhibit CYP3A4 enzyme activity, or medications such as cisapride or metoclopramide;
• Patients with dysphagia, active gastrointestinal disorders, malabsorption syndrome, or other conditions that may affect the absorption of the investigational drug;
• Interstitial pneumonitis, including clinically significant radiation pneumonitis;
• Severe asthma;
• Uncontrolled diabetes mellitus;
• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements;
• First-degree relatives with a history of sudden cardiac death before the age of 50. First-degree relatives are defined as those with a direct bloodline, such as parents and children, grandparents and grandchildren, or maternal grandparents and maternal grandchildren;
• Active bacterial, fungal, or viral infections, including active hepatitis B (HBsAg positive with HBV DNA > 1000 IU/mL or meeting local diagnostic criteria for active HBV infection), hepatitis C (HCV RNA positive), or HIV infection (HIV positive);
• Pregnant or breastfeeding women. Any patient who becomes pregnant during the trial must withdraw from the study;
• Known hypersensitivity to everolimus, other rapamycin derivatives, or any of the excipients in this product. Observed allergic reactions to everolimus or related compounds include but are not limited to: hypersensitivity, dyspnea, flushing, chest pain, or angioedema (e.g., airway or tongue swelling with or without respiratory compromise);
• Other factors, as determined by the investigator, that may lead to early study termination, such as presence of other severe diseases (including psychiatric disorders) requiring concomitant treatment, significantly abnormal lab values, or social/family issues that may affect patient safety or data collection.