Efficacy and Safety of Rapamycin to Complex Vascular Anomalies in Pediatric Patients

A Phase II Clinical Study to Evaluate the Efficacy and Safety of Rapamycin in Complex Vascular Anomalies in Pediatric Patients

KHE and TA are rare tumors and some of the cases may lead to life-threatening complications including Kasabach-Merritt Phenomenon. Typically treated with steroids and vincristine, a majority of the cases do not have good prognosis. Complex vascular malformations are always managed by surgery,sclerotherapy and embolization therapy. While many of the cases still lead to complications such as disfigurement, chronic pain, recurrent infections, coagulopathies. Different medical centers are exploring new therapy for these tough problems. This study is plotted to determine the efficacy and safety of rapamycin monotherapy in KHE/TA and complex vascular malformations in pediatric patients.

According to the classification （revised in 2014）by International Society for the Study of Vascular （ISSVA ）, vascular anomalies are classified into two distinct disease entities，including vascular tumors and vascular malformations differing in their biologic and pathologic features. Vascular tumors include infantile and congenital hemangiomas, Tufted angiomas (TA), and Kaposiform hemangioendotheliomas (KHE). Vascular malformations are classified according to their vascular tissue of origin which include capillary, venous, arteriovenous, lymphatic, and mixed malformations. Infantile hemangiomas, the most common vascular anomaly, generally have a good prognosis due to its specific biological characteristics（a predetermined life cycle from proliferation to subsequent involution). However，KHE and TA are rare vascular tumors with incidence less than 1/1000000 and along with complex lymphatic malformations and complex mixed malformations，are difficult to be successfully treated resulting in clinical problems such as disfigurement, chronic pain, recurrent infections, coagulopathies (thrombotic and hemorrhagic,including life-threatening Kasabach-Merritt Phenomenon), organ dysfunction. Rapamycin directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis and is recently applied to refractory vascular . Preclinical data and case reports have confirm that rapamycin is effective for KHE/TA and some slow-flow vascular malformations. The overall goal of this trial is to objectively determine the effectiveness and safety of rapamycin monotherapy in KHE/TA and complex vascular malformations in pediatric patients and to explore the rational doses. In this study, 30 patients (aged from 1 month to 14 years old) diagnosed with KHE/TA or complex vascular that respond poorly to propranolol hydrochloride and corticosteroid are enrolled. Oral rapamycin is given as a monotherapy at a initial dose of 0.8mg/m2, once daily for children under 3 years old and twice daily (every 12 hours) for those above 3 years. And further dosage is adjusted to target a trough concentration of rapamycin in plasma as 10-15ng/ml （OR 15-20ng/ml if the efficacy of treatment is not satisfactory with concentration at 10-15ng/ml. One course lasts for 12weeks and no more than 4 courses are given.Volumetric changes as the primary outcome measure will be analysed by magnetic resonance imaging (MRI) and/or ultrasonography. Frequency of adverse events as assessed by CTCAE v4.0 is calculated to evaluate the safety of rapamycin.

Inclusion Criteria:

1. Diagnosis: All patients must be diagnosed with Kaposiform Hemangioendotheliomas ，Tufted Angioma or complicated vascular malformation as determined by clinical, radiographic and histologic criteria (when possible)；

2. Patients must have vascular anomalies that respond poorly to propranolol hydrochloride and corticosteroid;

3. Organ function requirements:

   3.1 Adequate liver function defined as: Total bilirubin (sum of conjugated and unconjugated) ≤1.5 x ULN for age, and SGPT (ALT) <5 x ULN for age, and Serum albumin > or = 2 g/dL.

   3.2 Adequate Bone Marrow Function defined as: Peripheral absolute neutrophil count (ANC) > 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） 3.3 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 < age ≤ 10 years of age maximum serum creatinine (mg/dL) of 1.0 11 < age ≤ 15 years of age maximum serum creatinine (mg/dL) of 1.2 > 15 years of age maximum serum creatinine (mg/dL) of 1.5 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) < 0.3 g/l

4. Patients must be Human Immunodeficiency Virus negative and without immunodeficiency or infectious disease such as viral hepatitis.

5. Patients must have no gastrointestinal disease that would affect the absorption of rapamycin.

6. Performance Status: Karnofsky > or = 50 (>10 years of age) and Lansky > or = 50 for patients < or = 10 years of age.

7. Patients may not be currently receiving strong inhibitors of CYP3A4 or strong inducers of CYP3A4 and may not have received these medications within 1 week of entry.

8. Patients must not have corticosteroid, chemotherapy or radiotherapy within 2 weeks of entry.

9. Guardians must be informed consent.

Exclusion Criteria:

1. Known allergy to mTOR inhibitor
2. Under the treatment of other medicine for vascular anomalies.
3. Known chronic or infectious disease.
4. Patients who received prior per os treatment with an mTOR inhibitor.
5. Known digestive disease that would affect the absorption of rapamycin.
6. Guardians disagree to sign the informed consent.
7. Patients who in the opinion of the investigator would be at risk in the study or would affect the accuracy of the study results.-