Safety and Efficacy of Low-dose Sirolimus to Kaposiform Hemangioendothelioma

Safety and Efficacy of Low-dose Sirolimus to Kaposiform Hemangioendothelioma:A Prospective, Randomized Open Trial

to evaluate the safety and efficacy of Low-dose sirolimus in Kaposiform Hemangioendothelioma in Chinese children by a prospective, randomized open trial.

Study Overview

• Status: Completed
• Conditions: Hemangioma; Kaposiform Hemangioendothelioma
• Intervention / Treatment: Drug: Sirolimus(0.8mg/m2); Drug: Sirolimus(0.7mg/m2)

Detailed Description

The clinically commonly used dose of sirolimus for Kaposiform Hemangioendothelioma is 0.8 mg/m2 administered twice daily, and the blood concentration can be maintained at 10-15 ng/ml according to the pharmacokinetic formula.Related research reports that maintaining low blood concentration of sirolimus is effective in the treatment of certain vascular malformations and hemangioma, and complications are less. In the clinical practice, we found that the blood concentration was maintained at 7-10 ng/ml, and the patients still achieved good results and the chance of infections decreased. Therefore, this clinical trial was designed.In this trial, two different dosing regimens with corresponding blood concentration were designed to compare the safety and efficacy.In the high concentration group, the sirolimus dosage was adjusted monthly to achieve trough levels between 10 and 15 ng/mL(excluding 10 ng/ml), and it is still used at 0.8 mg/m2 administered twice daily.The low concentration group is 7-10 ng/ml (including 10 ng/ml), and the initial use of sirolimus is 0.7mg/m2 administered twice daily.The dose was adjusted according to the formula after two weeks.The follow-up and evaluation were performed according to a strictly established follow-up schedule after taking the drug.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Shanghai, China, 210012
    • Children's Hospital of Fudan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Kaposiform Hemangioendotheliomas with or without Kasabach-Merritt Phenomenon.
• 0 - 12 years of age at the time of study entry.
• Male or female.
• Consent of parents (or the person having parental authority in families): Signed and dated written informed consent.

Exclusion Criteria:

• with hematological diseases.
• with other solid tumors.
• with hypertension, diabetes, adrenal insufficiency, neurological diseases, liver and kidney dysfunction, and cardiopulmonary insufficiency.
• with tuberculosis,cytomegalovirus and Epstein-Barr virus infection before the treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: high blood concentration group; The blood concentration is maintained at 10-15ng/ml (not including 10ng/ml).	Drug: Sirolimus(0.8mg/m2); The initial use of sirolimus is 0.8mg/m2 administered twice daily.After two weeks of taking the drug, blood concentrations are measured and adjusted appropriately to maintain the targeted blood concentration.; Other Names: Rapamycin
Experimental: low blood concentration group; The blood concentration is maintained at 7-10ng/ml (including 10ng/ml).	Drug: Sirolimus(0.7mg/m2); The initial use of sirolimus is 0.7mg/m2 administered twice daily.After two weeks of taking the drug, blood concentrations are measured and adjusted appropriately to maintain the targeted blood concentration.; Other Names: Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
response to treatment	it is a variable outcome, including complete responses, partial response and no response. The definitions are : Complete Response： platelets counts is greater than 100×10^9/L.; significant volume reduction is greater than 80%.; Fibrinogen levels at 2-4g/L.; The surface skin of the tumor is lighter or the tumor is softer significantly. Partial Response: platelets counts is greater than 40×10^9/L.; significant volume reduction is greater than 50%.; Fibrinogen levels at less than 50% reduction from baseline.; The surface skin of the tumor and palpation of the tumor have no change or less change. No Response: platelets counts is less than 40×10^9/L.; significant volume reduction is less than 50% or the tumor is bigger.; Fibrinogen levels at grater then 50% reduction from baseline.; The surface skin of the tumor is darker or the tumor is harder.	1 year after taking the drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Monitoring patient's clinical biochemical indicators and symptoms	1 year after taking the drug

Collaborators and Investigators

• Sponsor: Children's Hospital of Fudan University

Publications and helpful links

General Publications

• Drolet BA, Trenor CC 3rd, Brandao LR, Chiu YE, Chun RH, Dasgupta R, Garzon MC, Hammill AM, Johnson CM, Tlougan B, Blei F, David M, Elluru R, Frieden IJ, Friedlander SF, Iacobas I, Jensen JN, King DM, Lee MT, Nelson S, Patel M, Pope E, Powell J, Seefeldt M, Siegel DH, Kelly M, Adams DM. Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma. J Pediatr. 2013 Jul;163(1):285-91. doi: 10.1016/j.jpeds.2013.03.080. No abstract available.
• Yoon HY, Hwang JJ, Kim DS, Song JW. Efficacy and safety of low-dose Sirolimus in Lymphangioleiomyomatosis. Orphanet J Rare Dis. 2018 Nov 14;13(1):204. doi: 10.1186/s13023-018-0946-8.
• Kazmierczak D, Maliszewska A. [Disturbances of tooth and maxillary development in Down's syndrome and their treatment]. Czas Stomatol. 1986 Nov;39(11):755-9. No abstract available. Polish.
• Ozgonenel B, Martin A. Low-dose sirolimus controls recurrent iron deficiency in a patient with blue rubber bleb nevus syndrome. Pediatr Blood Cancer. 2015 Nov;62(11):2054-5. doi: 10.1002/pbc.25590. Epub 2015 Jul 1. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Actual): December 10, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: June 25, 2019
• First Submitted That Met QC Criteria: September 2, 2019
• First Posted (Actual): September 4, 2019

Study Record Updates

• Last Update Posted (Estimate): January 30, 2023
• Last Update Submitted That Met QC Criteria: January 27, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Kaposiform Hemangioendothelioma; Kasabach-Merritt Syndrome; Sirolimus; Rapamycin
• Additional Relevant MeSH Terms: Virus Diseases; Infections; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; DNA Virus Infections; Thrombocytopenia; Blood Platelet Disorders; Herpesviridae Infections; Sarcoma; Neoplasms, Vascular Tissue; Hemangioma; Sarcoma, Kaposi; Hemangioendothelioma; Kasabach-Merritt Syndrome; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 2019-161

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No