Neoplasms

All Conditions

Rare Diseases

Hemangioendothelioma

Hemangioma

Neoplasms, Vascular Tissue

Neoplasms by Histologic Type

Anti-Arrhythmia Agents

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Propranolol

Sirolimus

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patients with propranolol-resistant IHHE are given propranolol combined with sirolimus

Patients with IHHE wil be treated with propranolol (1 mg / kg , twice a day, after meals), and then evaluation will be performed after 3 months (changes of the tumor size measured by ultrasound examination, and changes of tumor volume measured by abdominal enhancement CT).It will be admitted into the group once the tumor volume shrinks \<30%.Then propanolol combined with sirolimus will be given. Propranolol will be given at 1mg/kg,twice a day and sirolimus will be given at 0.8mg/m²(body surface area), twice a day. Recording and doing assessment of tumor size, adverse effects as well as complicated symptoms.

Sirolimus Oral Product

propranolol

Song Gu, Doctor

Hongxiong Gao, Master

Infantile hepatic hemangioendothelioma (IHHE) is an infantile hemangioma involving the liver.Since 2008, propranolol has been used for the treatment of hemangioma, and some researchers have also started to report the use of propranolol for the treatment of infantile hepatic hemangioma in children. Sirolimus can be used in patients with vascular malformations such as hemangiomas. IHHE is also an infantile hemangioma involving the liver,thus sirolimus may paly the role in treatment of IHHE.The clinical trial explores the efficacy of sequential treatment of sirolimus to refractory IHHE patients resistant with propranolol, to improve the therapeutic effect, reduce the side effects of traditional treatment methods (hormones, interferon), and reduce the number of operations and interventions and to provide a clinical basis for the application of the new therapeutics model of IHHE of "propranolol + sequential sirolimus treatment".

According to the World Health Organization(WHO) classification of digestive system tumors in the fourth edition in 2010, infantile hepatic hemangioendothelioma (IHHE) is an infantile hemangioma involving the liver. It is a benign tumor, which can be subgrouped into focal, multifocal, and diffusing in children, as well as combining vascular malformations of the skin, brain, digestive tract and other organs.Since 2008, propranolol has been used for the treatment of hemangioma, and some researchers have also started to report the use of propranolol for the treatment of infantile hepatic hemangioma in children.And more and more clinicians unanimously recommend propranolol as first-line medication for the treatment of IHHE.However, there are few solutions to propranolol-resistant IHHE. Sirolimus is a serine/threonine kinase which plays a pivotal role in cell mortality, angiogenesis and cell growth. Sirolimus can be used in patients with vascular malformations such as hemangiomas. Children with vascular malformations received 0.1mg/kg of sirolimus orally every day and maintained the blood concentration at 8-15ng/ml. The lesions gradually disappear with time going on. Therefore, sirolimus can be used as a second-line medicine for refractory hemangioma and vascular malformation.Interestingly, the investigator's previous study which is retrospective analysis of 30 patients has indicated the effective rate of propranolol alone in treating infantile hepatic endothelial tumor (IHHE) was 57.7%, while that of sequential treatment combined with sirolimus was 84.6%.So, this clinical trial is going to explore the efficacy of sequential treatment of sirolimus to refractory IHHE patients resistant with propranolol,to improve the therapeutic effect,furtherly, reduce the side effects of traditional treatment methods (hormones, interferon), as well as the number of operations and interventions and to provide a clinical guide for the novel therapeutics model of propranolol combined with sirolimus for sequential treatment of infantile hepatic hemangioendothelioma.

Recruiting patients with IHHE who have no response to propranolol after 3 months. Then propranolol combined with sirolimus will be given.

Sirolimus in the Treatment for Infantile Hepatic Hemangioendothelioma(IEEH)

Sirolimus in the Treatment for Propranolol-resistant Infantile Hepatic Hemangioendothelioma

Using PIVKA-II assay kit (ARCHITECT I2000SR REFURB, Abbott, America).

Using the AFP assay kit (ARCHITECT AFP, Abbott, America).

Shanghai Children's Medical Center

Symptoms and General Pathology

Blood and Lymph Conditions

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Syndrome

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Lipid Regulating Agents

Simvastatin

Everolimus

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Hydroxymethylglutaryl-CoA Reductase Inhibitors

Eligible patients on sirolimus or everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Eligible patients on sirolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Eligible patients on everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Everolimus Oral Product

Vera P Krymskaya, PhD, MBA

Maryl Kreider, MD, MSCE

Frank McCormack, MD

The purpose of this research study is to see if simvastatin can be taken safely in patients with either LAM or TSC, who are already being treated with everolimus or sirolimus. This is the first step in looking at simvastatin as a drug that may help patients, by impacting the growth and survival of cells that make up the lung lesions that cause problems in LAM and TSC patients. The study also seeks to learn more about how simvastatin works, when given to patients being treated with everolimus or sirolimus, and to evaluate the safety and any potential benefit to patients taking this 2-drug combination.

The primary objective of this study is to determine the safety of simvastatin in the treatment of LAM-S or LAM-TS in patients on a stable (for at least 3 months) dose of sirolimus or everolimus.

Secondary objectives include:

* To assess the effect of simvastatin on forced expiratory volume in 1 second (FEV1).
* To assess the effect of simvastatin on forced vital capacity (FVC).
* To assess the effect of simvastatin on diffusing lung capacity (DLCO).
* To assess the effect of simvastatin on vascular endothelial growth factor -D (VEGF-D) serum levels.
* To assess the effect of simvastatin with questionnaire- based assessments of dyspnea, fatigue, and quality of life (QOL).
* Assess signs of clinical benefit.

After providing written informed consent, study related tests/procedures will be done to ensure eligibility for the study. If found to be eligible, the participant will be given simvastatin at a starting dose of 20 mg, to be taken each evening by mouth. If after 2 months the simvastatin 20 mg dose is tolerated, the dose of simvastatin will be increased to 40 mg each evening by mouth. Doses may be adjusted as needed, should the participant experience side effects from simvastatin. The participant's dose of everolimus or sirolimus is not expected to change, as this is a dose that has been previously tolerated. If side effects occur as a result of the combination of drugs, the dosages may be adjusted by the study physician (investigator).

Safety of Simvastatin in LAM and TSC

The Safety of Simvastatin (SOS) in Patients With Pulmonary Lymphangioleiomyomatosis (LAM) and With Tuberous Sclerosis Complex (TSC)

Safety is a primary outcome measure which will be assessed by any major changes or deterioration in patient health.

Lung function will be measured by FEV1: forced expiratory volume in 1s mean and calculated as % predicted +_ SD (standard deviation).

The LAM Foundation

University of Pennsylvania

Simvastatin 20 mg oral daily for 2 months; if tolerated, followed by simvastatin 40 mg oral daily for 2 months

Simvastatin: Eligible patients will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Single Simvastatin Treatment Arm

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

The baseline measure was lung function accessed as the forced expiratory volumes (unit ml) in 1 second (FEV1) response and was calculated as the rate of change in FEV1, which was calculated as percentage of predicted.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Sirolimus in the Treatment for Infantile Hepatic Hemangioendothelioma(IEEH)	NCT04406870	Hemangioendothe...	Sirolimus Oral ... propranolol	1 Month - 36 Months	Shanghai Children's Medical Center
Sirolimus in the Treatment for Infantile Hepatic Hemangioendothelioma(IEEH)	NCT04406870	Hemangioendothe...	Sirolimus Oral ... propranolol	1 Month - 36 Months	Shanghai Children's Medical Center
Sirolimus in the Treatment for Infantile Hepatic Hemangioendothelioma(IEEH)	NCT04406870	Hemangioendothe...	Sirolimus Oral ... propranolol	1 Month - 36 Months	Shanghai Children's Medical Center
Safety of Simvastatin in LAM and TSC	NCT02061397	Lymphangioleiom... Tuberous Sclero...	Simvastatin Sirolimus Oral ... Everolimus Oral...	18 Years -	University of Pennsylvania

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