Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care
Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care
The phosphatidylinositol 3-kinase (PI3Kinase)/Protein Kinase B (AKT)/mammalian target of
 rapamycin (mTor) pathway plays a role on the development and the venous/lymphatic vascular
 organisations.

 The investigators want to study the efficacy and the safety of Rapamycin, an mTor inhibitor.
The complex vascular malformations induce chronical pains and organic dysfunctions causing
 significant morbidity and mortality. Therefore, the investigators need to establish
 guidelines in order to treat these pathologies. Standard treatments such as surgery or
 interventional radiology are of limited efficacy and related to a high level of recurrences
 as well as complications. Recent preclinical studies have shown the important role of the
 PI3Kinase/AKT/mTor pathway on the development and the venous/lymphatic vascular organisations
 suggesting an appealing therapeutic target to treat patients with venous, lympathic or
 complex vascular malformations.

 Investigators will realize a multicentric phase III study enrolling a higher number of
 patients to statistically evaluate the efficacy and the safety of the Rapamycin, an mTOR
 inhibitor, in the treatment of children and adults with vascular malformations for which
 conventional therapies such as surgery or sclerotherapy are ineffective or associated with
 high risk of important complications. Nearly 250 patients (200 adults and 50 children) will
 be enrolled in several european centers.
Inclusion Criteria:

 -  Patients with complex vascular anomalies that are refractory to standard care such as
 medical treatment, surgical resection and/or sclerotherapy/embolization (ineffective
 or accompanied by major complications)

 -  Patients must have adequate medullary function: Hemoglobine> 10,0 g/dl, neutrophils
 >1500/mm³ and platelets > 100.000/mm³

 -  Patients must have the following laboratory values:

 -  Total serum bilirubin ≤ 1.5 x ULN (or totally bilirubin ≤ 3 x ULN with direct
 bilirubin ≤ 1.5 x ULN in patients with well documented Gilbert Syndrome)

 -  Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN
 (or < 5.0 x ULN if hepatic metastases are present)

 -  Serum creatinine 1.5 x ULN. If the serum creatinine is ≥ 1.5 x ULN, then a 24-hour
 Creatinine Clearance must be conducted and the result must be ≥ 60 mL/min.

 -  Karnofsky > 50

 -  Patients have to be able to sign the informed consent

 -  Women in age of procreation have to be informed that contraceptive methods are
 mandatory during the study time

 Exclusion Criteria:

 -  Any of the following concurrent severe and/or uncontrolled medical conditions, which
 could compromise participation in the study or interfere with the study results:

 -  Impaired cardiac function or clinically significant cardiac diseases, including
 unstable angina pectoris, ventricular arrhythmia, valvular disease with documented
 compromise in cardiac function, myocardial infarction within the last 6 months,
 documented by persistent elevated cardiac enzymes or persistent regional wall
 abnormalities on assessment of LVEF function, history of documented congestive heart
 failure (New York Heart Association functional classification III-IV), documented
 cardiomyopathy, family history of congenital long or short QT, or known history of
 QT/QTc prolongation of Torsades de Pointes (TdP)

 -  Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly
 alter the absorption of sirolimus (e.g., ulcerative diseases, uncontrolled nausea,
 vomiting, diarrhea ≥ Grade 2, malabsorption syndrome, or small bowel resection)

 -  Known hypersensitivity to drugs or metabolites from similar classes as study
 treatment.

 -  Patient has other concurrent severe and /or uncontrolled medical condition that
 would,in the investigator's judgment, contraindicated participation in the clinical
 study (e.g. acute or chronic pancreatitis, liver cirrhosis, active chronic hepatitis,
 severely impaired lung function with a spirometry ≤ 50% of the normal predicted value
 and/or O2 saturation ≤ 88% at rest, etc.)

 -  Immunocompromised patients, including known seropositivity for HIV

 -  Pregnant or lactating women

 -  Prior treatment with PI3K and/or mTOR inhibitors