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

Zhujiang Hospital30 enrolled

Overview

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.

Eligibility

Sex: ALLMin age: 1 MonthMax age: 14 Years

Medical Language ↔ Plain English

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.-

Outcomes

Primary Outcomes

Volumetric changes in complicated vascular anomalies after rapamycin treatment

Response to rapamycin treatment was measured by volumetric magnetic resonance imaging (MRI) and/or ultrasonography analyses. Changes in size of vascular anomalies were classified as further growth (increase of ≥20%), no change (\<20% increase and \<20% decrease),and involution (decrease of ≥20%).

Time frame: Baseline,and every 6 months until half a year after the finish of rapamycin treatment

Time of clinical lab indexes to be improved and stable

For cases complicated with Kasabach-Merritt Phenomenon, clinical lab indexes including blood platelet and fibrinogen are followed up at least weekly before a improved and stable state is reached. Time (days) from the onset of treatment till these indexes to be improved and stable is calculated. Improved hematologic parameters are defined as a platelet count greater than 50,000/uL (or a 2 times increase in platelet count compared to baseline) and a fibrinogen level greater than 100mg/dl.

Time frame: at least weekly before a improved and stable state is reached,assessed up to 8 weeks

Occurrence of adverse reactions

Record the time, degree and outcome of adverse reactions according to Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.0.

Time frame: From the date of trial until the date of first documented progression or date of lost to follow-up,till half a year after finish of treatment.

Secondary Outcomes

Trough concentration of rapamycin in plasma

Trough concentration of rapamycin in plasma is monitored and according to which the dosage is adjusted，thus is part of the efficacy evaluation.

Time frame: 5 days after the onset of rapamycin or after the adjustment of drug doses;every 3 three months during the therapy if the concentration result is in the optimal target range during the treatment,assessed up to 100 months.

Evolution of clinical situation and the quality of life

Evolution of clinical situation and the quality of life is judged by the proxies of patients by describing clinical symptoms and by recording and viewing standardized digital photographs.

Time frame: Baselin,3,6,12months,and till half an year after finish of treatment

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts