Low- vs High-Dose Sirolimus With Prednisolone for KHE and KMP

Official title

Low-dose Versus High-dose Sirolimus Combined With Prednisolone for Kaposiform Hemangioendothelioma With Kasabach-Merritt Phenomenon: a Randomized Noninferiority Trial

Overview

This randomized clinical trial evaluates if low-dose sirolimus (target trough 4-8 ng/mL) combined with prednisolone is noninferior in efficacy but superior in safety compared to standard high-dose sirolimus (target trough 10-15 ng/mL) combined with prednisolone in pediatric patients with kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon (KHE with KMP), with participants randomized 1:1 to receive the assigned regimen, undergo routine blood and imaging monitoring, and be evaluated for clinical response and adverse events.

Detailed description

The goal of this randomized clinical trial is to evaluate if low-dose sirolimus combined with prednisolone is noninferior to high-dose sirolimus combined with prednisolone in managing kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon (KHE with KMP) in pediatric patients. In this study, the low-dose regimen targets a sirolimus trough concentration of 4-8 ng/mL, while the standard high-dose regimen targets a trough concentration of 10-15 ng/mL. The main questions it aims to answer are:

Does the combination of low-dose sirolimus (target trough 4-8 ng/mL) and prednisolone achieve a noninferior objective response rate (including platelet count recovery and tumor volume reduction) compared to the high-dose sirolimus (target trough 10-15 ng/mL) and prednisolone combination at the primary endpoint evaluation? Does the low-dose sirolimus combination significantly reduce treatment-related toxicities and adverse events compared to the high-dose sirolimus combination?

Researchers will compare a low-dose sirolimus plus prednisolone arm to a standard high-dose sirolimus plus prednisolone arm to see if lowering the sirolimus dose within this combination regimen can maintain comparable therapeutic control over KMP while minimizing dose-dependent adverse effects.

Participants will:

Be randomized in a 1:1 ratio to receive either oral low-dose sirolimus combined with prednisolone (targeting a trough level of 4-8 ng/mL) or standard high-dose sirolimus combined with prednisolone (targeting a trough level of 10-15 ng/mL).

Undergo regular clinical evaluations, including physical examinations and serial blood tests to monitor peripheral platelet counts and sirolimus trough levels.

Receive routine imaging studies (such as MRI or ultrasound) to assess changes in tumor volume.

Be closely monitored throughout the study period for combination therapy-related side effects and systemic corticosteroid-associated adverse events.

Interventions

• Drug Sirolimus (RAPAMUNE)
  Participants will receive oral sirolimus in combination with prednisolone. Patients will be randomized in a 1:1 ratio to either a low-dose sirolimus group, with dose adjustments to maintain a target plasma trough concentration of 4-8 ng/mL, or a high-dose sirolimus group, with dose adjustments to maintain a target plasma trough concentration of 10-15 ng/mL. Prednisolone will be administered according to the study protocol and tapered based on clinical response. The total treatment duration will

Primary outcome measures

• Proportion of Participants Achieving Platelet Count Recovery [Time frame: 2 months]

Secondary outcome measures (6)

• Proportion of Participants Achieving Fibrinogen Recovery [Time frame: 2 months]
• Change in D-Dimer Level From Baseline [Time frame: 2 months]
• Change in KHE Tumor Volume From Baseline [Time frame: 6 and 12 months]
• The changes in the patient's symptoms and/or complications. [Time frame: 6 and 12 months]
• Frequency of adverse events [Time frame: 12 months]
• Quality of life (QOL) in patients. [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Presenting a KHE with the following characteristics:

• Clinical features and histological findings consistent with progressive, non-resectable KHE associated with KMP.
• Patients must be 0 - 18 years of age at the time of study entry.
• Without functional impairment requiring treatment of corticosteroid.
• Organ function requirements:

1 Adequate liver function:

• Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)for age, and
• ALT and AST less than or equal to 2.5 x upper limit normal (ULN) for age.

2 Adequate renal function:

• 0-5 years of age maximum serum creatinine (mg/dL) of 0.8
• 6-10 years of age maximum serum creatinine (mg/dL) of 1.0
• 11-15 years of age maximum serum creatinine (mg/dL) of 1.2
• 16-18 years of age maximum serum creatinine (mg/dL) of 1.5
• Adequate bone marrow function: Absolute Neutrophil Count (ANC) greater than or equal to 1 x 10 to the ninth/Liter.
• Consent of parents (or the person having parental authority in families): Signed and dated written informed consent.

Exclusion criteria

• Allergy to sirolimus or other rapamycin analogues.
• Any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of randomization.
• Patients must not be known to be Human Immunodeficiency Virus positive or known immunodeficiency. Testing is not required unless a condition is suspected.
• Other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe malnutrition, chronic liver or renal disease, active upper gastrointestinal tract ulceration).
• Impairment of gastrointestinal function or chronic gastrointestinal disease that may significantly alter the absorption of sirolimus.
• Patients who have a history of malignancy.
• Patients with an inability to participate or to follow the study treatment and assessment plan.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 1 center

• West China Hospital of Sichuan University — Chengdu

Publications

• Lauven PM, Schwilden H, Stoeckel H. Threshold hypnotic concentration of methohexitone. Eur J Clin Pharmacol. 1987;33(3):261-5. doi: 10.1007/BF00637559. PMID 3691614
• Ji Y, Chen S, Yang K, Zhou J, Zhang X, Jiang X, Xu X, Lu G, Qiu L, Kong F, Zhang Y. A prospective multicenter study of sirolimus for complicated vascular anomalies. J Vasc Surg. 2021 Nov;74(5):1673-1681.e3. doi: 10.1016/j.jvs.2021.04.071. Epub 2021 May 31. PMID 34082006
• Wada Y, Iijima K, Yonezawa T. [The effects of nitroglycerin induced hypotension on the tissue blood flow in dogs under halothane anesthesia]. Masui. 1985 Sep;34(9):1208-15. No abstract available. Japanese. PMID 3936944
• Zhou J, Yang K, Dai S, Qiu T, Zhang X, Gong X, Chen S, Ji Y. Clinical features and management of kaposiform hemangioendothelioma and tufted angioma: Similarities and differences. J Am Acad Dermatol. 2022 Jul;87(1):172-174. doi: 10.1016/j.jaad.2021.07.012. Epub 2021 Jul 14. No abstract available. PMID 34273457
• Zhou J, Qiu T, Zhang Z, Lan Y, Huo R, Xiang B, Chen S, Qiu L, Xia C, Xu X, Li J, Ma Y, Yao W, Wang Z, Dong C, Qin Z, Tai M, Guo L, He X, Gu S, Li L, Hou F, Cai Y, Wang H, Wang J, Jiang X, Zheng J, Li K, Ji Y. Consensus statement for the diagnosis, treatment, and prognosis of kaposiform hemangioendothelioma. Int J Cancer. 2025 May 15;156(10):1986-1994. doi: 10.1002/ijc.35344. Epub 2025 Jan 20. PMID 39831682
• Zhou J, Lan Y, Qiu T, Zhang Z, Gong X, Zhang X, Yang C, Zhou Z, Zhang Y, Yang M, Fu J, He C, Peng Q, Hu F, Xia C, Kong F, Chen S, Ji Y. Efficacy and safety of high-vs low-dose sirolimus in patients with kaposiform hemangioendothelioma: A randomized clinical trial. J Am Acad Dermatol. 2025 Jul;93(1):124-131. doi: 10.1016/j.jaad.2025.03.023. Epub 2025 Mar 17. PMID 40107509
• Zhou J, Ji Y. Kaposiform hemangioendothelioma. J Am Acad Dermatol. 2026 Mar 12:S0190-9622(26)00396-8. doi: 10.1016/j.jaad.2026.03.020. Online ahead of print. No abstract available. PMID 41831614
• Ji Y, Chen S, Zhou J, Yang K, Zhang X, Xiang B, Qiu T, Gong X, Zhang Z, Lan Y, Hu F, Kong F, Qiu Q, Zhang Y. Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial. Blood. 2022 Mar 17;139(11):1619-1630. doi: 10.1182/blood.2021014027. PMID 35030255

Identifiers

NCT: NCT07656909 · RCT20260615

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗