Different Doses of Sirolimus for the Maintenance Treatment of Kaposiform Hemangioendothelioma

Phase 2

Recruiting

• Conditions: Hemangioendothelioma
• Interventions: Drug: Sirolimus

• Registration Number: NCT05324384
• Lead Sponsor: West China Hospital

Brief Summary

The purpose of this study is to compare the efficacy and safety of different doses of sirolimus in the maintenance treatment of kaposiform hemangioendothelioma.

Detailed Description

Kaposiform hemangioendothelioma (KHE) is a rare aggressive vascular neoplasm that occurs predominantly in infancy or early childhood, with an incidence of approximately 0.071/100,000. Currently, sirolimus is a promising treatment modality for KHE. Most scholars consider sirolimus blood concentration of 5-15 ng/ml to be an effective therapeutic concentration, while 10-15 ng/ml is the most commonly used blood concentration. However, long-term higher dose sirolimus treatment can cause some common adverse effects, such as oral mucositis which affects the quality of life of the patient. Finer control of the plasma concentration of sirolimus may contribute to the efficacy of treatment and reduce the incidence of complications. Previous studies have found good efficacy of low-dose sirolimus maintenance treatment for KHE. However, there is no high-level evidence to support this treatment strategy. Therefore, we conducted this study to find out whether an early reduction in sirolimus dose would benefit the prognosis of the patients.

Study Timeline

• Study Start: 2022-04-05
• Study First Submitted: 2022-04-05
• Study First Submitted QC: 2022-04-05
• Study First Posted: 2022-04-12
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-23
• Last Update Posted: 2024-01-24
• Primary Completion: 2025-04-30
• Study Completion: 2025-11-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Presenting a KHE with the following characteristics:

1. Male and female;

2. Between 0 and 14 years of age;

3. Diagnosis of KHE as determined by:

   • Biopsy;
   • Compatible MRI findings;
   • History and clinical features.

4. Patients were required to have adequate liver, renal and bone marrow function, and absence of active infection

5. Consent of parents (or the person with parental authority in families): signed and dated written informed consent.

Exclusion Criteria

1. Patients contraindicated for the administration of sirolimus (e.g., those with an allergy to sirolimus or other rapamycin analog)

2. Exposure to chemotherapy, embolization, corticosteroids, propranolol, sclerotherapy or any other investigational agents within 1 weeks before enrolment on study;

3. Patients had a history of a major surgery within 2 weeks before enrollment;

4. Patients who have a history of treatment with sirolimus or other mTOR inhibitor;

5. Any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of enrollment;

6. Concurrent severe and/or uncontrolled medical diseases that could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe malnutrition, chronic liver or renal disease, active upper gastrointestinal tract ulceration).

7. Impairment of gastrointestinal function or chronic gastrointestinal disease that may significantly alter the absorption of sirolimus.

8. Patients with inadequate liver function:

   Total bilirubin higher than or equal to 1.5 × the upper limit of the normal (ULN) for age and alanine aminotransferase and aspartate aminotransferase higher than or equal to 2.5 × the ULN for age.

9. Patients with inadequate 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; 11-14 years of age maximum serum creatinine (mg/dL) of 1.2;

10. Adequate bone marrow function:

    Absolute neutrophil count lower than 1 × 109/L;

11. History of a malignancy within 5 years;

12. HIV infection or known immunodeficiency;

13. Indication for treatment with corticosteroids, vincristine, interferon-α, sirolimus, or tacrolimus for an indication other than IH;

14. Patients with an inability to participate in or follow-up during the study treatment and assessment plan;

15. Inability to give informed consent.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Low dose of sirolimus	Sirolimus	The plasma trough concentration of sirolimus is maintained within the range of 10-15 ng/ml by adjusting sirolimus dose, for 6 months. Then, The plasma trough concentration of sirolimus is maintained within the range of 5-8 ng/ml by adjusting sirolimus dose, for 6 months.
Regular dose of sirolimus	Sirolimus	Sirolimus The plasma trough concentration of sirolimus is maintained within the range of 10-15 ng/ml by adjusting sirolimus dose, for 1 year.

Primary Outcome Measures

Name	Time	Method
The changes in KHE volume	12 months.	Response to therapy was measured by volumetric magnetic resonance imaging (MRI) analyses were performed at baseline and 6 and 12 months after treatment and were independently assessed by 2 radiologists. Changes in KHE size were classified as further growth (increase of ≥10%), no change (\<10% increase and \<10% decrease), partial involution (decrease of ≥10% and \<75%), nearly complete involution (decrease of ≥75% and \<100%), or complete involution (100%).

Secondary Outcome Measures

Name	Time	Method
Frequency of adverse events	Baseline, 6 months, 12 months.	Frequency of adverse events (e.g. gastrointestinal disorders, blood and lymphatic system disorders, metabolic disorders or other abnormal laboratory results, skin disorders and general disorders, etc.) collected by investigator and reported by parents. All adverse events were collected and graded according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). The causality of the adverse event was determined by the multidisciplinary staff and was classified as definitively not related, probably not related, possibly related, probably related, or definitively related. Any dose reductions, interruptions, or cessations enacted at the discretion of the investigators were recorded.
The changes of D-dimer levels.	Baseline, 3 monthss, 6 months, 9 months, 12 months.	D-dimer levels
Quality of life (QOL) in patients	Baseline, 6 months, 12 months.	Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Infant Scales (\<2 years) or Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Scales (2-18 years) were used.
The changes in the patient's musculoskeletal complication.	Baseline, 3 monthss, 6 months, 9 months, 12 months.	The severity of musculoskeletal complication was scored by using a 4-point scale: 1, asymptomatic or mild symptoms, clinical or diagnostic observations only; 2, moderate symptoms, limiting age-appropriate instrumental activities of daily living; 3, severe or medically significant symptoms, disabling or limiting self-care activities of daily living; and 4, life-threatening consequences, with urgent intervention indicated.
The changes of fibrinogen levels.	Baseline, 3 monthss, 6 months, 9 months, 12 months.	Fibrinogen levels
The changes of platelet counts.	Baseline, 3 monthss, 6 months, 9 months, 12 months.	Platelet counts

Trial Locations

Locations (1)

West China Hospital of Sichuan University; 🇨🇳 Chengdu, Sichuan, China