Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies

Inclusion Criteria

Inclusion will be strictly limited to children and young adults with vascular anomalies with complications that require systemic therapy for control.

Diagnosis: All patients must have one of the following vascular anomalies as determined by clinical, radiographic and histologic criteria (when possible):

• Kaposiform Hemangioendotheliomas with Kasabach-Merritt Phenomenon
• Kaposiform Hemangioendotheliomas without Kasabach-Merritt Phenomenon
• Tufted Angioma with Kasabach-Merritt Phenomenon
• Tufted Angioma without Kasabach-Merritt Phenomenon
• Capillary Lymphatico-Venous Malformation (CLVM)
• Venous Lymphatic Malformation (VLM)
• Microcystic Lymphatic Malformation (MLM)
• Multifocal Lymphangiomatosis and Thrombocytopenia (MLT)/Cutaneovisceral Angiomatosis and Thrombocytopenia (CAT)
• Capillary Lymphatic Arterial Venous Malformations (CLAVM)
• PTEN Overgrowth syndrome with vascular anomaly
• Lymphangiectasia Syndromes

If archived tissue is available, histological diagnosis will be confirmed by the pathology lab at the enrolling site.

Complications: Patients must have vascular anomalies that have potential to cause significant morbidity. In addition to the above diagnosis, one or more of the following criteria needs to be met:

• Coagulopathy
• Chronic pain
• Recurrent cellulitis (>3 episodes/year)
• Ulceration
• Visceral and/or bone involvement
• Cardiac dysfunction

Age: Patients must be 0 - 31 years of age at the time of study entry. Enrollment includes patients of both genders and all ethnic groups.

Organ function requirements:

Adequate liver function defined as:

• Total bilirubin (sum of conjugated and unconjugated) ≤1.5 x ULN for age, and
• SGPT (ALT) or = 2 g/dL.

Fasting LDL and cholesterol:

• Fasting LDL cholesterol of or = 1000/microL
• Hemoglobin > or = 8.0 gm/dL (may receive RBC transfusions)
• Platelet count > or = 50, 000/microL (transfusion independent defined as not receiving a platelet transfusion within a 7 day period prior to enrollment)

Note: There is NO platelet requirement for patients with Kasabach-Merritt Phenomenon

Adequate Renal Function Defined as:

• A serum creatinine based on age as follows:
• ≤ 5 years of age maximum serum creatinine (mg/dL) of 0.8
• 6 15 years of age maximum serum creatinine (mg/dL) of 1.5

AND cystatin C equal to or less than the upper limit of normal for the patient. If cystatin C does not initially meet this criterion, it may be repeated or a more sensitive screening by nuclear GFR must be ≥ 70 ml/min.

• Urine protein to creatinine ratio (UPC) or = 50 (>10 years of age) and Lansky > or = 50 for patients or = 6 months from involved field radiation to vascular tumor.
• CYP3A4 inhibitors: Patients may not be currently receiving strong inhibitors of CYP3A4, and may not have received these medications within 1 week of entry. (See Appendix II). These include:
• Macrolide Antibiotics: clarithromycin, telithromycin, erythromycin, troleandomycin.
• Gastrointestinal prokinetic agents: cisapride, metoclopramide.
• Antifungals: itraconazole, ketoconazole, fluconazole (doses > 200 mg/day), voriconazole, clotrimazole
• Calcium channel blockers: verapamil, diltiazem, nicardipine
• Other drugs: rifampin, bromocriptine, cimetidine (Tagamet®), danazol, cyclosporine oral solution, lansoprazole (Prevacid®).
• Grapefruit juice.
• CYP3A4 inducers: Patients must also avoid strong inducers of CYP3A4, and may not have received these medications within 1 week of entry. These include:
• Anticonvulsants: carbamazepine, phenobarbital, phenytoin
• Antibiotics: rifabutin, rifapentine.
• Herbal preparations: St. John's Wort (Hypericum perforatum, hypericine).
• Enzyme inducing anticonvulsants: Patients may not be taking enzyme-inducing anticonvulsants, and may not have received these medications within 1 week of entry, as these patients may experience different drug disposition. These medications include:
• Carbamazepine (Tegretol®)
• Felbamate (Felbtol®)
• Phenobarbito