A Study to Evaluate the Efficacy and Safety of Everolimus in Patients With Teratment-refractory Vascular Anomalies

Overview

Background and Objectives Vascular anomalies are a heterogeneous group of disorders classified into vascular tumors and vascular malformations according to the ISSVA classification. Although most follow a benign course, a subset causes serious complications including organ dysfunction, chronic pain, thrombocytopenia, and hemorrhage. Kaposiform hemangioendothelioma (KHE) complicated by Kasabach-Merritt Phenomenon (KMP) carries a mortality rate of 14-24%. Surgical resection is the primary treatment when organ damage is not anticipated; however, when surgery is not feasible, pharmacologic therapy is considered. Agents such as interferon, corticosteroids, vincristine, cyclophosphamide, and propranolol have been used with variable efficacy, and no established therapy exists for patients refractory to these treatments. The PI3K-Akt-mTOR and RAS-MEK-ERK pathways have been identified as key molecular mechanisms underlying vascular anomalies. Targeted therapies against these pathways are emerging, including anti-VEGF antibodies, PI3K/Akt inhibitors (e.g., alpelisib, miransertib), and mTOR inhibitors. Sirolimus has demonstrated clinical benefit in 50-80% of patients with vascular anomalies, with a 96% symptom response rate in KMP-associated vascular tumors. Everolimus, another mTOR inhibitor, is already approved and established for tuberous sclerosis-associated angiomyolipoma and SEGA in pediatric patients, with a well-characterized safety profile. Given its shared mechanism with sirolimus and emerging case reports supporting efficacy in KHE with KMP, this phase 2 study aims to evaluate the efficacy and safety of everolimus in patients with treatment-refractory vascular anomalies. Study Design This is a single-center, open-label, uncontrolled phase 2 clinical trial enrolling 67 patients over 60 months from IRB approval, stratified into two cohorts: Cohort 1 (sirolimus-naïve, n=39) and Cohort 2 (prior sirolimus failure, n=28). Everolimus is administered orally at age- and CYP3A4/P-gp inducer-adjusted doses, with maintenance dosing titrated to a target trough level of 5-15 ng/mL. The primary endpoint is overall response rate (ORR) at 6 months. Secondary endpoints include toxicity per NCI CTCAE v4.0, ORR at 12 months, platelet recovery rate at 4 weeks (KMP patients), 1-year overall survival, and 3-year progression-free survival.

1. Study Design This is a single-center, open-label, uncontrolled phase 2 clinical trial. The study period is 60 months from IRB approval; patients may not be enrolled within 1 year of the planned study end date. A total of 67 patients will be enrolled and stratified into two cohorts based on prior sirolimus exposure: Cohort 1 (sirolimus-naïve, n=39) and Cohort 2 (prior sirolimus failure, n=28). 2. Eligibility Criteria \- Inclusion Criteria: ① Diagnosis per the 2014 ISSVA classification: Group 1 (hemangioendothelioma, tufted angioma): histologically confirmed tumor, OR Kasabach-Merritt Syndrome (histologically confirmed or histologic diagnosis not feasible) Group 2 (vascular tumors not in Group 1, or vascular malformations): histologically confirmed, OR radiologically diagnosed when biopsy is not feasible * Age ≥1 year ③ Failure of at least one prior therapy (e.g., vincristine, corticosteroids, interferon), stratified as: Cohort 1: sirolimus-naïve Cohort 2: prior sirolimus failure ④ At least one measurable target lesion ≥1 cm in longest diameter per RECIST 1.1 on CT or MRI * ECOG Performance Score 0, 1, or 2 * WOCBP must have a negative pregnancy test prior to enrollment; adequate contraception required during the study and for 8 weeks after completion ⑦ Written informed consent obtained - Exclusion Criteria: ① Pregnancy or breastfeeding (WOCBP must use adequate contraception) * Documented allergy or hypersensitivity to everolimus ③ Inadequate organ function: Bone marrow: ANC \<1,000/µL or platelets \<75,000/µL Renal: serum creatinine \>1.5×ULN; if \>1.5×ULN, 24-hour creatinine clearance \<60 mL/min Hepatic: total bilirubin \>1.5×ULN or ALT \>3.0×ULN * KMP associated with vascular tumors or malformations is not an exclusion criterion, including: thrombocytopenia (\<100,000/µL), hypofibrinogenemia, anemia (Hb \<8 g/dL), consumptive coagulopathy, or overlying skin changes (edema, warmth, erythema, purplish/dark discoloration) * Uncontrolled hyperlipidemia (fasting cholesterol \>300 mg/dL or triglycerides \>2.5×ULN) * Uncontrolled diabetes (fasting glucose \>1.5×ULN) * Active uncontrolled infection * Hepatitis B (HBsAg positive) or hepatitis C (anti-HCV positive) * Known HIV infection (positive serology) * Clinically significant symptomatic pulmonary dysfunction; PFTs and room air SpO₂ performed if clinically indicated; exclusion if FEV₁ ≤70% or DLCO ≤70% of predicted (assessed in patients ≥8 years) ⑪ Prior solid organ or hematopoietic stem cell transplantation (bone marrow, liver, kidney, lung, or heart) ⑫ Concomitant investigational agents (e.g., mTOR inhibitors: sirolimus, temsirolimus) ⑬ Concurrent chemotherapy (e.g., mTOR inhibitors: sirolimus, temsirolimus) * Concurrent other malignancy not meeting eligibility criteria 3. Treatment Everolimus is administered orally with doses adjusted by age and concomitant CYP3A4/P-gp inducer use: -Starting dose: Age \<10 years: 6.0 mg/m²/day (9.0 mg/m²/day with CYP3A4/P-gp inducers) Age 10 to \<18 years: 5.0 mg/m²/day (8.0 mg/m²/day with CYP3A4/P-gp inducers) Age ≥18 years: 3.0 mg/m²/day (5.0 mg/m²/day with CYP3A4/P-gp inducers) -Maintenance dose: Adjusted to achieve a target trough level of 5-15 ng/mL 4. Endpoints \- Primary endpoint: Overall response rate (ORR) at 6 months \- Secondary endpoints: Toxicity assessment per NCI CTCAE v4.0 ORR at 12 months Rate of platelet recovery at 4 weeks (KMP patients) 1-year overall survival (OS) 3-year progression-free survival (PFS)