Sirolimus for Castleman Disease

Not currently recruiting at 3 trial locations

Overseen By Tracey Sikora

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must be taking: Anti-IL-6 therapy

Must not be taking: Sirolimus monotherapy

Disqualifiers: Pregnancy, Uncontrolled infection, HIV, 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: 3

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates how sirolimus, an oral medication, can help treat idiopathic multicentric Castleman disease (iMCD), a rare condition that causes enlarged lymph nodes and other symptoms. The study aims to determine if sirolimus is effective for those who haven't responded well to other treatments targeting interleukin-6, have experienced a relapse, or cannot tolerate these therapies. It suits individuals who can take oral medication and have active iMCD not controlled by previous treatments. Participants should have documented evidence of the disease and experience related symptoms or changes, such as weight loss or changes in lymph node size. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking any systemic therapies intended to treat Castleman disease, except for corticosteroids, at least 28 days before enrolling. If you are on anti-IL-6 therapy, you need to stop it at least 14 days before enrolling, unless you cannot or are unwilling to do so.

Is there any evidence suggesting that sirolimus is likely to be safe for humans?

Research has shown that sirolimus is generally safe for individuals with conditions like idiopathic multicentric Castleman disease (iMCD). One study found that patients taking sirolimus did not experience major side effects and even showed symptom improvement. A review of nine studies involving 575 children found that oral sirolimus is usually safe for treating various childhood diseases. Additionally, data from similar conditions revealed no serious toxic effects linked to sirolimus. Overall, these findings suggest that sirolimus is well-tolerated by many patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Castleman disease?

Unlike the standard treatments for Castleman Disease, which typically involve chemotherapy or immunotherapy, sirolimus is unique because it targets the mTOR pathway. Researchers are excited about sirolimus because it is an immunosuppressant that can potentially regulate the immune system more precisely than existing treatments. Additionally, sirolimus is administered orally, which might offer a more convenient option compared to some current therapies that require intravenous administration. This distinct mechanism and delivery method make sirolimus a promising candidate for improving the management of Castleman Disease.

What evidence suggests that sirolimus might be an effective treatment for Castleman disease?

Research has shown that sirolimus, which participants in this trial will receive, can help patients with idiopathic multicentric Castleman disease, especially those unresponsive to other treatments. In past studies, patients taking sirolimus experienced symptom relief and their disease entered remission. The drug targets a protein called mTOR, often overactive in this disease, affecting cell growth. Sirolimus is usually well tolerated, with patients experiencing only minor side effects. This suggests sirolimus could be a promising option for managing this condition. ^{2 3 4 6 7}

Who Is on the Research Team?

David C Fajgenbaum, MD, MBA, MSc

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for people aged 2-80 with idiopathic multicentric Castleman disease who haven't responded well to anti-IL-6 therapy or can't tolerate it. Participants must have active disease, be able to take oral medication, and not be pregnant or nursing. They shouldn't have had sirolimus before, any recent other systemic therapies except corticosteroids, severe infections mimicking iMCD, certain cancers within the last year, serious psychiatric disorders affecting consent ability, or very poor health as defined by specific medical criteria.

Inclusion Criteria

My condition did not improve with anti-IL-6 therapy, or I couldn't tolerate it.

You have a medical history that matches the criteria for a specific disease called iMCD (idiopathic multicentric Castleman disease).

I can take pills by mouth.

Exclusion Criteria

I do not have HIV, HHV-8, or severe combined immunodeficiency syndrome.

Subjects cannot have any other condition or finding that in the opinion of the investigator would make participation in this trial inappropriate

I am not currently in, nor planning to join, another clinical trial for my condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily oral sirolimus for 12 months

12 months

Visits at 3, 6, 9, and 12 months ± 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Sirolimus

Trial Overview The study tests the effect of Sirolimus on patients with idiopathic multicentric Castleman disease who haven’t seen improvement with standard treatments. It aims to understand how this drug impacts their condition.

How Is the Trial Designed?

Group I: Sirolimus Experimental Treatment 1 Intervention

Oral sirolimus: For adults, loading dose of 5 mg/m\^2, rounded to the nearest mg, on day 1. For adults, starting on day 2, oral sirolimus daily at 2.5 mg/m\^2/day (rounded to the nearest mg), target trough level 10-15 ng/mL by HPLC, for 12 months. For children, 2 mg/m\^2/day, target trough level 5-15 ng/mL by HPLC.

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?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

Sirolimus, an immunosuppressive drug, can cause severe side effects like capillary leak syndrome, as observed in two psoriasis patients, highlighting the need for careful monitoring during treatment.

In one patient, skin analysis showed a significant increase in apoptotic cells in lesional skin after sirolimus treatment, suggesting that the drug may induce apoptosis in activated T cells, contributing to its adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic toxicity following administration of sirolimus (formerly rapamycin) for psoriasis: association of capillary leak syndrome with apoptosis of lesional lymphocytes. Kaplan, MJ., Ellis, CN., Bata-Csorgo, Z., et al.[2019]

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

A systematic review of 9 studies involving 575 pediatric patients indicates that oral sirolimus is generally safe for treating childhood diseases, with oral mucositis being the most common adverse event reported in 8.2% of cases.

Adverse events were significantly more frequent in patients with higher sirolimus concentrations (≥10 ng/mL), highlighting the importance of monitoring drug levels to minimize serious side effects, especially in children with vascular anomalies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Evaluation of Oral Sirolimus in the Treatment of Childhood Diseases: A Systematic Review. Zhang, Z., Li, Y., Zhang, G., et al.[2023]

In a study involving 209 kidney transplant recipients in Korea, Rapamune (Sirolimus) demonstrated an acceptable safety profile, with 54.07% of subjects reporting adverse events, most of which were mild and resolved by the end of the study.

The efficacy of Rapamune was notable, with a low incidence of biopsy-proven acute rejection at 2.87% and a high graft survival rate of 99.51%, indicating its effectiveness in preventing kidney allograft rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Rapamune® (Sirolimus) in kidney transplant recipients: results of a prospective post-marketing surveillance study in Korea. Jeon, HJ., Lee, HE., Yang, J.[2019]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38691144/

Sirolimus is effective for refractory/relapsed idiopathic ... Sirolimus is well tolerated with minor adverse effects. In conclusion, sirolimus is effective for R/R iMCD patients with good tolerance.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03933904

NCT03933904 | Sirolimus in Previously Treated Idiopathic ... The purpose of this study is to understand the impact of sirolimus on idiopathic multicentric Castleman disease.

3. withpower.com withpower.com/trial/phase-3-castleman-disease-8-2019-d0538

Sirolimus for Castleman Disease · Info for Participants Trial Overview The study tests the effect of Sirolimus on patients with idiopathic multicentric Castleman disease who haven't seen improvement with standard ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9987611/

Refractory idiopathic multicentric Castleman disease ... Moreover, the patients tolerated the sirolimus without significant side effects, have experienced symptomatic benefits, and have been in remission for 64, 17, ...

5. ashpublications.org ashpublications.org/blood/article/135/19/1673/452765/Increased-mTOR-activation-in-idiopathic

Increased mTOR activation in idiopathic multicentric ... mTOR-Is have been used successfully in treatment-refractory malignancies and autoimmune syndromes that demonstrate clinicopathological overlap ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7387047/

Study protocol for clinical trial - PMC This clinical trial will provide evidence of efficacy and safety of sirolimus as a potential new therapeutic agent for patients with TCZ-resistant iMCD.

7. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/04/NCT03933904/Prot_SAP_002.pdf

A phase II, single-arm open-label multi-center study of ... This dosing schedule is based on safety and efficacy data of sirolimus in diseases with similarities to iMCD. No severe toxicities were ...