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

NCT04448873 | Completed Phase 4

• 1 other identifier: LK200421
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Kaposiform Hemangioendothelioma; Kasabach-Merritt Syndrome

Keywords

Kaposiform Hemangioendothelioma; Kasabach-Merritt Syndrome; Sirolimus; Rapamycin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Remission of KHE and the dose of sirolimus at one year follow-up

  From admission to follow-up one year

• Relapse of KHE and the dose of sirolimus at one year follow-up

  From admission to follow-up one year

• Side effects of sirolimus

  From admission to follow-up one year

• Platelet count

  From admission to follow-up one year

• Fibrinogen level

  From admission to follow-up one year

Other Outcomes (3)

• Remission of KHE and no use of sirolimus at two or three year follow-up

  From admission to follow-up two and three years

• Remission of KHE and the dose of sirolimus at two or three year follow-up

  From admission to follow-up two and three years

• Relapse of KHE and the dose of sirolimus at two or three year follow-up

  From admission to follow-up two and three years

Study Arms (2)

Maintenance treatment group

ACTIVE COMPARATOR

After at least 2 years of remission of KHE, the participant receives sirolimus as usual. The serum concentration is supposed to be 5-7 ng/ml. If the effect or side effects of sirolimus require discontinuation, it is allowed to modify intervention, and if so, the patient stays in the maintenance group.

Drug: Sirolimus

Guided discontinuation group

EXPERIMENTAL

After at least 2 years of remission of KHE, the discontinuation measurement should be guided by the clinician with the following principles: 1. 10% monthly reduction of the previous dose at most. 2. At least 5 half-lives between each reduction (2 weeks). 3. Blood concentration should be monitored monthly. Adjustment can be suggested according to the linear relationship between the dose and the blood concentration. 4. At least 6 months for the duration of guided discontinuation. 5. Regular assessments and evaluations should be done. If the condition relapses or worsens during this process, dose of sirolimus should be adjusted to the previously effective dose. After a 3-month stabilization phase, 5% monthly reduction of the previous dose could be considered.

Drug: Sirolimus

Interventions

Sirolimus DRUG

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

Also known as: Rapamycin

Guided discontinuation group; Maintenance treatment group

Eligibility Criteria

• Age: Up to 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Children's Hospital of Fudan University: lead

Study Sites (1)

Children's Hospital of Fudan University

Shanghai, Shanghai Municipality, 210012, China

Location

Related Publications (15)

• 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.

  PMID: 31489702 BACKGROUND

• 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.

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• 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.

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• 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.

  PMID: 22871490 BACKGROUND

• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

  PMID: 24476346 BACKGROUND

• 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.

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MeSH Terms

Conditions

Kaposiform Hemangioendothelioma; Kasabach-Merritt Syndrome

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Hemangioma; Neoplasms, Vascular Tissue; Neoplasms by Histologic Type; Neoplasms; Thrombocytopenia; Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Kai Li, MD, PhD

  Children's Hospital of Fudan University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Only the outcome assessors are blinded, neither clinicians nor patients, because they should be attentive of the risk of relapse in the discontinuation group. Also, it seems unethical if researchers were not to discover the group of patients in the maintenance group who can discontinue sirolimus without relapsing. Clinicians should be given the possibility to adjust dose and ensure the benefits of patients. Therefore, this trial only includes assessors blinding.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 10, 2020
• First Posted: June 26, 2020
• Study Start: July 1, 2020
• Primary Completion: February 1, 2023
• Study Completion: July 1, 2023
• Last Updated: September 26, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)