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

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

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.

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.

Inclusion Criteria:

• Presenting a KHE with the following characteristics:

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

• Organ function requirements:

  1 Adequate liver function:

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

  2 Adequate renal function:

  1. 0-5 years of age maximum serum creatinine (mg/dL) of 0.8
  2. 6-10 years of age maximum serum creatinine (mg/dL) of 1.0
  3. 11-15 years of age maximum serum creatinine (mg/dL) of 1.2
  4. 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.