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.
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
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 ⑥ 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
Pregnancy or breastfeeding (WOCBP must use adequate contraception)
Documented allergy or hypersensitivity to everolimus
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)
Single group
Everolimus
DrugEverolimus (dose varies by age and concomitant use of CYP3A4/P-gp inducers) -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
Overall Response Rate (ORR)
ORR is defined as the proportion of patients achieving complete response (CR) or partial response (PR) per RECIST 1.1 criteria on CT or MRI at 6 months from treatment initiation.
Overall Response Rate (ORR)
ORR is defined as the proportion of patients achieving complete response (CR) or partial response (PR) per RECIST 1.1 criteria on CT or MRI at 6 months from treatment initiation. ORR is defined as the proportion of patients achieving complete response (CR) or partial response (PR) per RECIST 1.1 criteria on CT or MRI at 6 months from treatment initiation. ORR is defined as the proportion of patients achieving complete response (CR) or partial response (PR) per RECIST 1.1 criteria on CT or MRI at 6 months from treatment initiation.
Overall Survival (OS)
Proportion of patients alive at 1 year from treatment initiation
Overall Response Rate (ORR)
ORR is defined as the proportion of patients achieving complete response (CR) or partial response (PR) per RECIST 1.1 criteria on CT or MRI at 6 months from treatment initiation.
Toxicity
Incidence and severity of adverse events assessed per NCI CTCAE v4.0
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