Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma

Kaposiform Hemangioendothelioma Clinical Trial

Official title:

Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma: a Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04448873
• Other study ID #: LK200421
• Status: Completed
• Phase: Phase 4
• Start date: July 1, 2020
• Est. completion date: July 1, 2023

Study information

• Verified date: September 2023
• Source: Children's Hospital of Fudan University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized controlled trial aims to compare guided discontinuation with maintenance treatment of sirolimus in pediatric patients with KHE.

Description:

Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumor that occurs in infants and children. KHE is characterized by sheets of spindle cells with an infiltrative pattern in the dermis, subcutaneous fat, and muscle. It is locally aggressive and can cause Kasabach-Merritt phenomenon, a serious life-threatening coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia. Sirolimus, one of the mTOR inhibitors, has become a new and very effective treatment, which is especially reliable for KHE with KMP and has acceptable side effects. However, there is yet no strong evidence on the best practice of treatment length of sirolimus. This randomized controlled trial aims to compare guided discontinuation with maintenance treatment in pediatric patients with KHE in order to provide a basis for the optimal treatment duration of sirolimus, as well as the clinical characteristics of pediatric patients who can safely reduce the dose till withdrawal.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 1, 2023
• Est. primary completion date: February 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 12 Years

Eligibility

Inclusion Criteria:

• Participant diagnosed with KHE with or without KMP

• Participant age 0-12 years

• Participant with detailed medical records of the disease at the time of screening

• Participant with at least two years of remission of KHE and no previous toxicity or adverse events

• Participant with normal liver and kidney function

• Participant with signed and dated informed consent from the guardian(s)

Exclusion Criteria:

• Participant with other hematological diseases

• Participant with other solid tumor

• Participant with general disease such as hypertension, diabetes, adrenal insufficiency, neurological diseases, liver and kidney dysfunction, and cardiopulmonary insufficiency.

• Participant with infectious diseases

• Unwilling participant

Related Conditions & MeSH terms

• Hemangioendothelioma
• Kaposiform Hemangioendothelioma
• Kasabach-Merritt Syndrome
• Sarcoma, Kaposi

Intervention

Drug:
• Sirolimus
After at least 2 years of remission of KHE, we compare guided discontinuation with maintenance treatment in pediatric patients with KHE.

Locations

Country	Name	City	State
China	Children's Hospital of Fudan University	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital of Fudan University

Country where clinical trial is conducted

China, 

References & Publications (15)

Blatt J, Stavas J, Moats-Staats B, Woosley J, Morrell DS. Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer. 2010 Dec 15;55(7):1396-8. doi: 10.1002/pbc.22766. — View Citation

Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, Hallmeyer S, Holter Chakrabarty J, Leighl NB, Mammen JS, McDermott DF, Naing A, Nastoupil LJ, Phillips T, Porter LD, Puzanov I, Reichner CA, Santomasso BD, Seigel C, Spira A, Suarez-Almazor ME, Wang Y, Weber JS, Wolchok JD, Thompson JA; National Comprehensive Cancer Network. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018 Jun 10;36(17):1714-1768. doi: 10.1200/JCO.2017.77.6385. Epub 2018 Feb 14. — View Citation

Croteau SE, Liang MG, Kozakewich HP, Alomari AI, Fishman SJ, Mulliken JB, Trenor CC 3rd. Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals. J Pediatr. 2013 Jan;162(1):142-7. doi: 10.1016/j.jpeds.2012.06.044. Epub 2012 Aug 4. — View Citation

Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007 Dec 20;357(25):2562-75. doi: 10.1056/NEJMoa067411. — View Citation

Gianfreda D, Nicastro M, Galetti M, Alberici F, Corradi D, Becchi G, Baldari G, De Filippo M, Ferretti S, Moroni G, Foti R, Di Gangi M, Jeannin G, Saffroy R, Emile JF, Buzio C, Vaglio A. Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial. Blood. 2015 Sep 3;126(10):1163-71. doi: 10.1182/blood-2015-01-620377. Epub 2015 Jun 3. — View Citation

Holt DW, Mandelbrot DA, Tortorici MA, Korth-Bradley JM, Sierka D, Levy DI, See Tai S, Horowitz GL. Long-term evaluation of analytical methods used in sirolimus therapeutic drug monitoring. Clin Transplant. 2014 Feb;28(2):243-51. doi: 10.1111/ctr.12305. Epub 2014 Jan 30. — View Citation

MacDonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther. 2000;22 Suppl B:B101-121. doi: 10.1016/s0149-2918(00)89027-x. — View Citation

Mariani LG, Schmitt IR, Garcia CD, Kiszewski AE. Low dose sirolimus treatment for refractory tufted angioma and congenital kaposiform hemangioendothelioma, both with Kasabach-Merritt phenomenon. Pediatr Blood Cancer. 2019 Aug;66(8):e27810. doi: 10.1002/pbc.27810. Epub 2019 May 14. No abstract available. — View Citation

Mauri L, D'Agostino RB Sr. Challenges in the Design and Interpretation of Noninferiority Trials. N Engl J Med. 2017 Oct 5;377(14):1357-1367. doi: 10.1056/NEJMra1510063. No abstract available. — View Citation

Mizuno T, Emoto C, Fukuda T, Hammill AM, Adams DM, Vinks AA. Model-based precision dosing of sirolimus in pediatric patients with vascular anomalies. Eur J Pharm Sci. 2017 Nov 15;109S:S124-S131. doi: 10.1016/j.ejps.2017.05.037. Epub 2017 May 17. — View Citation

Ryu YJ, Choi YH, Cheon JE, Kim WS, Kim IO, Park JE, Kim YJ. Imaging findings of Kaposiform Hemangioendothelioma in children. Eur J Radiol. 2017 Jan;86:198-205. doi: 10.1016/j.ejrad.2016.11.015. Epub 2016 Nov 10. — View Citation

Schmid I, Klenk AK, Sparber-Sauer M, Koscielniak E, Maxwell R, Haberle B. Kaposiform hemangioendothelioma in children: a benign vascular tumor with multiple treatment options. World J Pediatr. 2018 Aug;14(4):322-329. doi: 10.1007/s12519-018-0171-5. Epub 2018 Jul 27. — View Citation

Sturup AE, Jensen HD, Dolmer S, Birk M, Albert N, Nielsen M, Hjorthoj C, Eplov L, Ebdrup BH, Mors O, Nordentoft M. TAILOR - tapered discontinuation versus maintenance therapy of antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder in remission of psychotic symptoms: study protocol for a randomized clinical trial. Trials. 2017 Sep 29;18(1):445. doi: 10.1186/s13063-017-2172-4. — View Citation

Wang D, Chen X, Li Z. Population pharmacokinetics of sirolimus in pediatric patients with kaposiform hemangioendothelioma: A retrospective study. Oncol Lett. 2019 Sep;18(3):2412-2419. doi: 10.3892/ol.2019.10562. Epub 2019 Jul 4. — View Citation

Wang Z, Yao W, Sun H, Dong K, Ma Y, Chen L, Zheng S, Li K. Sirolimus therapy for kaposiform hemangioendothelioma with long-term follow-up. J Dermatol. 2019 Nov;46(11):956-961. doi: 10.1111/1346-8138.15076. Epub 2019 Sep 5. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Remission of KHE and no use of sirolimus at two or three year follow-up	This outcome is a binary variable. The primary outcome measure will be analyzed with binary logistic regression to estimate the odds ratio between the two groups.	From admission to follow-up two and three years
Other	Remission of KHE and the dose of sirolimus at two or three year follow-up	At two or three years' follow-up, the participant may be on remission, but still taking sirolimus. The condition is a binary variable and the dose of sirolimus is a continuous variable.	From admission to follow-up two and three years
Other	Relapse of KHE and the dose of sirolimus at two or three year follow-up	At two or three years' follow-up, the participant may suffer from relapse of KHE and still takes sirolimus. The period of time to the relapse will be recorded as a time variable, and the cox regression survival analysis model will be used.The dose of sirolimus is a continuous variable. Whether this variable is normally distributed will be checked.	From admission to follow-up two and three years
Primary	Remission of KHE and no use of sirolimus at one year follow-up.	The primary outcome is a binary variable. The primary outcome measure will be analyzed with binary logistic regression to estimate the odds ratio between the two groups.	From admission to follow-up one year
Secondary	Remission of KHE and the dose of sirolimus at one year follow-up	At one year's follow-up, the participant may be on remission, but still taking sirolimus. The condition is a binary variable and the dose of sirolimus is a continuous variable.	From admission to follow-up one year
Secondary	Relapse of KHE and the dose of sirolimus at one year follow-up	At one year's follow-up, the participant may suffer from relapse of KHE and still takes sirolimus. The period of time to the first relapse will be recorded as a time variable, and the cox regression survival analysis model will be used.The dose of sirolimus is a continuous variable. Whether this variable is normally distributed will be checked.	From admission to follow-up one year
Secondary	Side effects of sirolimus	The outcome 4 will be described. Adverse events will be reported according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). Incidence of complications such as oral ulcers, abnormal liver enzymes, infections will be recorded. The blood concentration of sirolimus will be adjusted accordingly.	From admission to follow-up one year
Secondary	Platelet count	Platelet count is one of the major indicators of response to treatment and will be used in a prognosis model to predict the clinical characteristics of patients with benefits. It is supposed to be greater than 100×10^9/L.	From admission to follow-up one year
Secondary	Fibrinogen level	Fibrinogen level will be used in a prognosis model to predict the clinical characteristics of patients with benefits. It is supposed to be at 2-4g/L.	From admission to follow-up one year
Secondary	Tumor volume	Tumor volume will be used in a prognosis model to predict the clinical characteristics of patients with benefits. The size of the tumor is supposed to shrink according to imaging evaluation. The tumor is supposed to be softer by palpation.	From admission to follow-up one year
Secondary	Complaints	Complaints are subjective feelings. Whether there is pain, swelling, lameness or skin color change will be recorded as binary variables and used in a prognosis model to predict the clinical characteristics of patients with benefits.	From admission to follow-up one year