Different Doses of Sirolimus for the Treatment of Cystic Lymphatic Malformations

Overview

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.

Interventions

• Drug Sirolimus (RAPAMUNE)
  Use of different doses of the same drug

Primary outcome measures

• The proportion of patients achieving an objective response at month 12 [Time frame: 12 months]

Secondary outcome measures (5)

• The proportion of patients achieving an objective response at month 6 [Time frame: 6 months]
• lesion responses [Time frame: 6 and 12 months]
• Quality of life (QOL) in patients [Time frame: 12 months]
• Disease sequelae [Time frame: 12 months]
• Frequency of adverse events [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Presenting a LM with the following characteristics:

• Male and female;
• Between 0 and 18 years of age;
• 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

• Patients contraindicated for the administration of sirolimus (e.g., those with an allergy to sirolimus or other rapamycin analog)
• Exposure to chemotherapy, embolization, corticosteroids, propranolol, sclerotherapy or any other investigational agents within 1 weeks before enrolment on study;
• Patients had a history of a major surgery within 2 weeks before enrollment;
• Patients who have a history of treatment with sirolimus or other mTOR inhibitor;
• Any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of enrollment;
• 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).
• Impairment of gastrointestinal function or chronic gastrointestinal disease that may significantly alter the absorption of sirolimus.
• 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.

• 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;

• Adequate bone marrow function:

Absolute neutrophil count lower than 1 × 109/L;

• History of a malignancy within 5 years;
• HIV infection or known immunodeficiency;
• Indication for treatment with corticosteroids, vincristine, interferon-α, sirolimus, or tacrolimus for an indication other than IH;
• Patients with an inability to participate in or follow-up during the study treatment and assessment plan;
• Inability to give informed consent.

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

• Ghariani Fetoui N, Boussofara L, Gammoudi R, Belajouza C, Ghariani N, Denguezli M. Efficacy of sirolimus in the treatment of microcystic lymphatic malformation of the tongue. J Eur Acad Dermatol Venereol. 2019 Sep;33(9):e336-e337. doi: 10.1111/jdv.15628. Epub 2019 Apr 22. No abstract available. PMID 30980684
• Cai R, Yang X, Gu H, Chen H, Lin X. Comment on "Sirolimus for the treatment of verrucous venous malformation: A retrospective cohort study": Are we missing the lymphatic malformation component? J Am Acad Dermatol. 2023 Mar;88(3):e133-e134. doi: 10.1016/j.jaad.2018.08.050. Epub 2018 Sep 18. No abstract available. PMID 30240774
• Gu Y, Sebaratnam DF. Topical rapamycin and microcystic lymphatic malformations. J Am Acad Dermatol. 2024 Jan;90(1):e29-e30. doi: 10.1016/j.jaad.2023.06.066. Epub 2023 Sep 17. No abstract available. PMID 37717734
• Ozeki M, Endo S, Yasue S, Nozawa A, Asada R, Saito AM, Hashimoto H, Fujimura T, Yamada Y, Kuroda T, Ueno S, Watanabe S, Nosaka S, Miyasaka M, Umezawa A, Matsuoka K, Maekawa T, Hirakawa S, Furukawa T, Fumino S, Tajiri T, Takemoto J, Souzaki R, Kinoshita Y, Fujino A. Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial. Front Med (Lausann PMID 38390569
• Yonekura S, Komori T, Ishida Y, Kogame T, Kabashima K. Treatment With Topical Sirolimus for Recurrent Lymphatic Malformation of the External Urethral Meatus. JAMA Dermatol. 2022 Nov 1;158(11):1331-1332. doi: 10.1001/jamadermatol.2022.2793. PMID 36044195
• Strychowsky JE, Rahbar R, O'Hare MJ, Irace AL, Padua H, Trenor CC 3rd. Sirolimus as treatment for 19 patients with refractory cervicofacial lymphatic malformation. Laryngoscope. 2018 Jan;128(1):269-276. doi: 10.1002/lary.26780. Epub 2017 Aug 7. PMID 28782106
• Ozeki M, Fukao T. Generalized Lymphatic Anomaly and Gorham-Stout Disease: Overview and Recent Insights. Adv Wound Care (New Rochelle). 2019 Jun 1;8(6):230-245. doi: 10.1089/wound.2018.0850. Epub 2019 Jun 6. PMID 31236308
• Maruani A, Tavernier E, Boccara O, Mazereeuw-Hautier J, Leducq S, Bessis D, Guibaud L, Vabres P, Carmignac V, Mallet S, Barbarot S, Chiaverini C, Droitcourt C, Bursztejn AC, Lengelle C, Woillard JB, Herbreteau D, Le Touze A, Joly A, Leaute-Labreze C, Powell J, Bourgoin H, Gissot V, Giraudeau B, Morel B. Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomiz PMID 34524406

Identifiers

NCT: NCT06673290 · RCT20241029

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗