Sirolimus in the Treatment for Infantile Hepatic Hemangioendothelioma(IEEH)

Hemangioendothelioma of Liver Clinical Trial

— PRL-SRL-IHHE  

Official title:

Sirolimus in the Treatment for Propranolol-resistant Infantile Hepatic Hemangioendothelioma

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04406870
• Other study ID #: PRL-SRL-IHHE
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: July 2020
• Est. completion date: June 30, 2025

Study information

• Verified date: May 2020
• Source: Shanghai Children's Medical Center
• Contact: Song Gu, Doctor
• Phone: +86-18930830716
• Email: gusong[@]shsmu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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".

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 36
• Est. completion date: June 30, 2025
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 36 Months

Eligibility

Inclusion Criteria:

• Confirmed as IHHE

• Age between 1 month and 36 months

• Receiving propranolol for 3 months but the tumor size shrinks <30%

• With written informed consent

Exclusion Criteria:

• Confirmed as hepatoblastoma

• Have accepted surgical resection

• Clinical data missing

• Patients with Kasabach-Merritt phenomenon

• Receiving propranolol for 3 months and the tumor size shrinks >30%

Related Conditions & MeSH terms

• Hemangioendothelioma
• Hemangioendothelioma of Liver

Intervention

Drug:
• Sirolimus Oral Product
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.
• propranolol
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.

Locations

Country	Name	City	State
China	Shanghai Children's Medical Center Shanghai Jiaotong University School of Medicine	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Children's Medical Center

Country where clinical trial is conducted

China, 

References & Publications (8)

Avagyan S, Klein M, Kerkar N, Demattia A, Blei F, Lee S, Rosenberg HK, Arnon R. Propranolol as a first-line treatment for diffuse infantile hepatic hemangioendothelioma. J Pediatr Gastroenterol Nutr. 2013 Mar;56(3):e17-20. doi: 10.1097/MPG.0b013e31824e50b7. — View Citation

Chatmethakul T, Bhat R, Alkaabi M, Siddiqui A, Peevy K, Zayek M. Infantile Hepatic Hemangioendothelioma: An Uncommon Cause of Persistent Pulmonary Hypertension in a Newborn Infant. AJP Rep. 2016 Jul;6(3):e260-3. doi: 10.1055/s-0036-1585578. — View Citation

Chaturvedi K, Steinberg JS, Snyder CS. Cost-effectiveness of treating infantile haemangioma with propranolol in an outpatient setting. Cardiol Young. 2018 Oct;28(10):1105-1108. doi: 10.1017/S1047951118000987. Epub 2018 Jul 26. — View Citation

Chen CC, Kong MS, Yang CP, Hung IJ. Hepatic hemangioendothelioma in children: analysis of thirteen cases. Acta Paediatr Taiwan. 2003 Jan-Feb;44(1):8-13. — View Citation

Maaloul I, Aloulou H, Hentati Y, Kamoun T, Mnif Z, Hachicha M. Infantile hepatic hemangioendothelioma successfully treated by low dose of propranolol. Presse Med. 2017 Apr;46(4):454-456. doi: 10.1016/j.lpm.2017.01.010. Epub 2017 Mar 15. — View Citation

Mehrabi A, Kashfi A, Schemmer P, Sauer P, Encke J, Fonouni H, Friess H, Weitz J, Schmidt J, Büchler MW, Kraus TW. Surgical treatment of primary hepatic epithelioid hemangioendothelioma. Transplantation. 2005 Sep 27;80(1 Suppl):S109-12. — View Citation

Özdemir ZC, Düzenli Kar Y, Söhret NC, Kebapçi M, Bör Ö. Beta blocker and steroid therapy in the treatment of infantile hepatic hemangioendothelioma. Drug Discov Ther. 2017 Jul 31;11(3):161-164. doi: 10.5582/ddt.2017.01025. Epub 2017 Jul 25. — View Citation

Requena L, Kutzner H. Hemangioendothelioma. Semin Diagn Pathol. 2013 Feb;30(1):29-44. doi: 10.1053/j.semdp.2012.01.003. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change of tumor size	measuring the tumor size by ultrasound	1 month
Secondary	Change of PIVKA-II	Using PIVKA-II assay kit (ARCHITECT I2000SR REFURB, Abbott, America).	1 month
Secondary	Change of alpha-1 fetoprotein (AFP)	Using the AFP assay kit (ARCHITECT AFP, Abbott, America).	1 month