Weekly Sirolimus for Lymphatic and Venous Malformations

Overseen By Stephnie Munie, BS

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Medical University of South Carolina

Must be taking: Sirolimus

Must not be taking: CYP3A4 inhibitors, inducers

Disqualifiers: Transplant, Immunodeficiency, Infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 6 months

24 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking certain medications that affect how sirolimus works. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Sirolimus for treating lymphatic and venous malformations?

Research shows that Sirolimus has been effective in treating lymphatic malformations, especially in children, by reducing the size and symptoms of these growths. It has been used successfully in cases where other treatments like surgery or sclerotherapy (a procedure to shrink blood vessels) were not effective. ^{1 2 3 4 5}

Is sirolimus safe for treating lymphatic and venous malformations?

Sirolimus has shown a generally favorable safety profile in treating vascular anomalies, though some severe adverse events have been reported during its off-label use. In a study using topical sirolimus gel, no adverse events were observed, suggesting it may be safe for certain types of vascular malformations. ^{1 5 6 7 8}

How is the drug Sirolimus unique in treating lymphatic and venous malformations?

Sirolimus is unique because it is an oral medication that targets the mTOR pathway, which helps control cell growth and proliferation, making it effective for treating vascular malformations that are difficult to manage with traditional methods like surgery or sclerotherapy. It offers a non-invasive option for patients with extensive or recurrent malformations, where other treatments have limited success. ^{2 5 9 10 11}

What is the purpose of this trial?

This trial is testing if taking sirolimus once a week can help people with venous and lymphatic malformations. These patients have few treatment options. Sirolimus aims to reduce abnormal growths by affecting the immune system. The study will also check for side effects and patient satisfaction over several months. Sirolimus has been used in various studies to treat lymphatic malformations and has shown potential in stabilizing lung function in patients with lymphangioleiomyomatosis.

Research Team

Chelsea Shope, MSCR

Principal Investigator

Medical University of South Carolina

Eligibility Criteria

This trial is for individuals aged 2 years and older with venous, lymphatic, or venolymphatic malformations. It excludes those with contraindications to sirolimus, on certain other medications, pregnant women or those who might become pregnant without effective contraception, and children with a history of transplant or immunodeficiency.

Inclusion Criteria

You have malformations in your veins, lymphatic system, or both.

Patients aged 2 years and older

Exclusion Criteria

Children who have had previous immune system problems.

Children who have had a severe or life-threatening infection in the past.

If you are a child taking medications that inhibit CYP3A4.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive once weekly dosed sirolimus for the treatment of venous and lymphatic malformations

6 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 months

2 visits (in-person)

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Sirolimus

Trial Overview The study tests if taking the oral medication Sirolimus once a week can treat venous and lymphatic malformations effectively. The treatment lasts for six months with an option to continue thereafter. Patient satisfaction and side effects will also be evaluated.

Participant Groups

Group I: Treatment Group Experimental Treatment 1 Intervention

Sirolimus is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in European Union as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Canada as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Japan as Rapamune for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

Findings from Research

Sirolimus shows promise in treating pediatric lymphatic malformations, with 19 studies reviewed involving 97 patients, but the overall efficacy and safety profile is still uncertain due to a lack of high-quality research.

Mild-to-moderate adverse events were reported in 94 cases, highlighting the need for systematic reporting of side effects to help clinicians manage treatment risks, especially in younger children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus treatment for paediatric head and neck lymphatic malformations: a systematic review. Saibene, AM., Rosso, C., Felisati, G., et al.[2023]

A 10-year-old boy with an orbital venolymphatic malformation was initially treated with local sclerotherapy, but the condition relapsed, highlighting the need for effective long-term management strategies.

The relapse was successfully managed with oral sirolimus, suggesting that this medication may be a promising treatment option for lymphatic malformations, although further studies are needed to establish optimal dosing and broader applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of orbital lymphatic malformation with oral sirolimus: a case report. Alba-Linero, C., García-Lorente, M., Rachwani-Anil, R., et al.[2023]

Sirolimus is effective in reducing the volume of pediatric cervicofacial lymphatic malformations (LMs), with 78% of patients showing a reduction of 20% or more on MRI, and 32% achieving a reduction of 50% or more.

The treatment also leads to significant clinical improvements, with 97% of patients reporting some benefit, and particularly helps airway LMs, as 33% of tracheostomy-dependent patients were able to be decannulated after starting sirolimus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus for Pediatric Cervicofacial Lymphatic Malformation: A Systematic Review and Meta-Analysis. Kamhieh, Y., Mitra, R., Burnett, T., et al.[2023]

In a study of 56 children with complex lymphatic malformations treated with oral sirolimus, the total effective rate for reducing lesions was 89.3%, indicating high efficacy of the treatment.

Sirolimus was found to be safe, with no serious adverse reactions reported, suggesting it could be a preferable alternative to surgical interventions for managing these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of sirolimus in the treatment of complex lymphatic malformations: Single center report of 56 cases. Tian, R., Liang, Y., Zhang, W., et al.[2021]

Sirolimus, a new medical therapy, has shown promise in treating lymphatic malformations in a female infant, indicating its potential as an effective alternative to traditional treatments like sclerotherapy and surgery.

The case report highlights both improvements and complications during the first 9 months of treatment, suggesting that while sirolimus can be beneficial, careful monitoring is necessary to manage any adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: A Successful Medical Treatment for Head and Neck Lymphatic Malformations. Curry, S., Logeman, A., Jones, D.[2020]

Sirolimus has been found effective in reducing the size and symptoms of various vascular malformations, with significant improvements observed in 67% of patients with venous malformations and over 80% with lymphatic malformations after 6 months of treatment.

While side effects occurred in 53% of patients, they were generally mild, but there is a notable risk of recurrence of symptoms in 49% of patients who stopped treatment, highlighting the need for ongoing clinical trials to better understand the long-term safety and efficacy of sirolimus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A narrative review of the role of sirolimus in the treatment of congenital vascular malformations. Geeurickx, M., Labarque, V.[2022]

In a study of 14 patients receiving off-label sirolimus therapy for various vascular anomalies, 17 severe adverse events (SAEs) were identified, with viral pneumonia being the most common, leading to one death in an infant.

Most SAEs occurred within the first year of treatment, highlighting the need for careful monitoring, especially in young patients and those with complex underlying conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe adverse events during sirolimus "off-label" therapy for vascular anomalies. Rössler, J., Baselga, E., Davila, V., et al.[2022]

A pilot study involving four patients with various vascular malformations found that topical sirolimus gel (0.2%) was safe, with no adverse events reported and no detectable blood levels of sirolimus.

The treatment showed clinical effectiveness comparable to systemic sirolimus, with 50% of patients experiencing mild improvement, particularly in blue rubber bleb nevus syndrome, indicating potential for topical sirolimus in treating venous and capillary malformations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Verification of the efficacy of topical sirolimus gel for systemic rare vascular malformations: a pilot study. Wataya-Kaneda, M., Maeda, S., Nakamura, A., et al.[2023]

A 30-year-old male with a rare intraorbital lymphatic-venous malformation was successfully treated with sirolimus, resulting in complete clinical and radiologic remission after 18 months.

The treatment was generally well-tolerated, with only mild cold-like symptoms and temporary liver enzyme elevation noted, and no major adverse effects were reported, indicating sirolimus may be a safe option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraorbital lymphatic-venous malformation in an adult patient: is sirolimus the key? Ruiz Velasco Santacruz, A., Nieva Pascual, I., Cifuentes Canorea, P., et al.[2023]

Sirolimus, an antiangiogenetic and antiproliferative agent, has been shown to be a safe and effective treatment for pediatric patients with vascular malformations (VMs) that cover wide anatomical areas, with five out of six patients achieving partial responses after an average treatment duration of 13 months.

The effectiveness of sirolimus appears to increase with the proportion of lymphatic components in the vascular malformation, and all patients tolerated the treatment well with acceptable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center experience with sirolimus therapy for vascular malformations. Yesil, S., Tanyildiz, HG., Bozkurt, C., et al.[2022]

Sirolimus treatment showed promising results in patients with extensive lymphatic malformations, with 60 out of 71 patients experiencing partial remission, indicating its potential efficacy as a therapeutic option.

Common side effects of sirolimus included hyperlipidemia and neutropenia, highlighting the need for careful monitoring during treatment, as well as the necessity for further randomized controlled studies to better understand its long-term safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Lymphatic Malformations with the mTOR Inhibitor Sirolimus: A Systematic Review. Wiegand, S., Wichmann, G., Dietz, A.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Sirolimus treatment for paediatric head and neck lymphatic malformations: a systematic review. [2023]

2. Brazil pubmed.ncbi.nlm.nih.gov

Treatment of orbital lymphatic malformation with oral sirolimus: a case report. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Sirolimus for Pediatric Cervicofacial Lymphatic Malformation: A Systematic Review and Meta-Analysis. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of sirolimus in the treatment of complex lymphatic malformations: Single center report of 56 cases. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Sirolimus: A Successful Medical Treatment for Head and Neck Lymphatic Malformations. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

A narrative review of the role of sirolimus in the treatment of congenital vascular malformations. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Severe adverse events during sirolimus "off-label" therapy for vascular anomalies. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Verification of the efficacy of topical sirolimus gel for systemic rare vascular malformations: a pilot study. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Intraorbital lymphatic-venous malformation in an adult patient: is sirolimus the key? [2023]

10. England pubmed.ncbi.nlm.nih.gov

Single-center experience with sirolimus therapy for vascular malformations. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Treatment of Lymphatic Malformations with the mTOR Inhibitor Sirolimus: A Systematic Review. [2021]