Different Doses of Sirolimus for the Treatment of Cystic Lymphatic Malformations

Phase 2

Recruiting

• Conditions: Lymphatic Malformation
• Interventions: Drug: Sirolimus (RAPAMUNE)

• Registration Number: NCT06673290
• Lead Sponsor: West China Hospital

Brief Summary

The purpose of this study is to compare the efficacy and safety of different concentration gradients of sirolimus in the treatment of cystic lymphatic malformation.

Detailed Description

Cystic lymphatic malformation is a disease caused by abnormal development of the lymphatic system, characterized by abnormal dilation and/or structural disorder of lymphatic vessels. These abnormalities may lead to accumulation of lymphatic fluid, causing local swelling, pain, and even affecting organ function. Cystic lymphatic malformation can occur anywhere in the body, including skin, soft tissue, internal organs, etc.

Sirolimus, also known as rapamycin, is an immunosuppressant mainly used to prevent rejection after organ transplantation. In recent years, studies have shown that sirolimus has certain potential in the treatment of lymphatic malformations.

However, long-term high-dose sirolimus treatment can cause some common complications, such as oral mucositis, which affects the quality of life of patients. More fine-grained control of rapamycin plasma concentrations may help improve the therapeutic effect and reduce the incidence of complications. Therefore, the investigators conducted this study to understand whether low-dose rapamycin is beneficial to the prognosis of patients.

Study Timeline

• Study First Submitted: 2024-10-31
• Study First Submitted QC: 2024-10-31
• Study First Posted: 2024-11-04
• Study Start: 2024-11-30
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-27
• Last Update Posted: 2024-12-31
• Primary Completion: 2026-12-30
• Study Completion: 2026-12-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

• Presenting a LM with the following characteristics:

  1. Male and female;
  2. Between 0 and 18 years of age;
  3. LM diagnosis was confirmed by local investigators and by consensus of our multidisciplinary vascular anomaly group at the West China Hospital of Sichuan University based on:

Biopsy; Compatible MRI findings; History and clinical features.

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 (RAPAMUNE)	The plasma trough concentration of sirolimus is maintained within the range of 5-8 ng/ml by adjusting sirolimus dose, for 1 year.
High dose of sirolimus	Sirolimus (RAPAMUNE)	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 proportion of patients achieving an objective response at month 12	12 months	Objective response was defined as ≥20% reduction in LM volume compared to that at baseline.

Secondary Outcome Measures

Name	Time	Method
The proportion of patients achieving an objective response at month 6	6 months	Objective response was defined as ≥20% reduction in LM volume compared to that at baseline.
lesion responses	6 and 12 months	The primary endpoint was classified as follow: -Complete involution: 100% resolution of the measured LM; -Nearly complete involution was defined as decrease of ≥75% and \<100%; -Partial involution was defined as decrease of ≥20% and \<75%; -No change was defined as \<20% increase and \<20% decrease in the volumes of LM lesions; -Further growth was defined as ≥20% increase in the volume of index LM compared with the baseline volume measured. Lesion responses were overall lesion response rate and good lesion response rate. Overall lesion response comprised complete, nearly complete and partial involutions. Good lesion response comprised complete and nearly complete involutions.
Quality of life (QOL) in patients	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.
Disease sequelae	12 months	Disease sequelae were assessed by site investigators at month 12. The site investigators assessed patients' extremity swelling (if any), general physical activity and exercise levels.
Frequency of adverse events	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 5.0 (CTCAE v5.0). 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.

Trial Locations

Locations (1)

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