Sirolimus for Blood Disorder

Overseen By Courtney DiNardo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers, Cannabidiol, others

Disqualifiers: Lymphoma, Hematologic malignancies, Myocardial infarction, 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: 22 weeks

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests sirolimus to determine its safety and effectiveness for individuals with the blood disorder RUNX1-FPD. Researchers aim to discover if a low dose of sirolimus can help manage this condition. Participants will take the medication daily and attend several clinic visits throughout the year. This trial may suit adults with a confirmed RUNX1 gene variant and no history of certain blood cancers or uncontrolled bleeding. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that affect sirolimus levels, such as strong inhibitors or inducers of CYP3A4, and some other specific drugs, at least 7 days before starting the study. If you are on any of these medications, you may need to stop or switch them before participating.

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

Research has shown that sirolimus is commonly used to prevent organ rejection in kidney transplant patients. It has been used for a long time and is usually well-tolerated at the prescribed doses. Some people may experience side effects like high blood pressure or high cholesterol, but regular check-ups can manage these issues.

Initial studies indicate that sirolimus does not affect growth in patients when used long-term. While higher doses can cause more side effects, clinical trials like this one generally use lower doses.

Sirolimus is well-established in medicine, which helps doctors better understand its safety profile. However, like any medication, there is always a chance of side effects. Regular monitoring during trials helps detect any issues early. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for blood disorders, which often include therapies like corticosteroids or immunosuppressants with broad effects, Sirolimus specifically targets the mTOR pathway. This targeted approach can help regulate abnormal cell growth and immune response more precisely. Researchers are excited about Sirolimus because it offers a more refined mechanism of action, potentially reducing side effects and improving outcomes compared to traditional options. This precision makes Sirolimus a promising option for patients and a focus of current research.

What evidence suggests that sirolimus might be an effective treatment for RUNX1-FPD?

Research has shown that sirolimus, the treatment under study in this trial, can aid certain blood disorders. For instance, one study of patients with immune thrombocytopenia (ITP) found that 55% responded positively to sirolimus within one month. It has also benefited individuals with autoimmune cytopenias, where the immune system mistakenly attacks blood cells. In another study, 83% of patients showed improvement in various aspects of their condition. These findings suggest that sirolimus may help manage conditions affecting the blood or immune system. ^{6 7 8 9 10}

Who Is on the Research Team?

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with RUNX1 Familial Platelet Disorder who have a platelet count of ≥50,000/µL and normal heart, liver, and kidney function can join. They must not have had certain blood disorders or treatments like sirolimus recently and should be free from serious infections or uncontrolled bleeding.

Inclusion Criteria

Participants has provided signed, informed consent before initiation of any study specific procedures

Platelet count of ≥50,000/µL

I am willing to give bone marrow samples at the start and end of my treatment.

Exclusion Criteria

I have not had a blood clot in an artery in the last 6 months.

Known allergy to sirolimus

Total cholesterol >300 mg/dL or triglyceride >400 mg/dL

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive low-dose sirolimus to evaluate safety and hematopoietic function

22 weeks

2 visits during Week 1, 1 visit during Weeks 2-4, then every 2 weeks until Week 22

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 weeks

1 visit at Week 24 and 1 visit at Week 52

What Are the Treatments Tested in This Trial?

Interventions

• Sirolimus

Trial Overview The trial is testing the safety and effects of low-dose Sirolimus on patients with thrombocytopenia due to RUNX1-FPD. Participants will provide bone marrow samples before and after treatment to assess changes in hematopoietic function.

How Is the Trial Designed?

Group I: Arm 1 Experimental Treatment 1 Intervention

Participants will visit the study clinic 2 times during Week 1, one (1) time during Weeks 2-4, and then 1 time every 2 weeks after that (Weeks 6, 8, 10, and so on) until Week 22 (Month 6). Then participants will have a follow-up visit at Week 24 and again at Week 52 (Month 12). Participants will take sirolimus by mouth every day, at about the same time each day. Swallow the tablet(s) whole with a full glass of water (about 1 cup). Do not crush or chew the tablet(s). Participants may take sirolimus with or without food.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

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]

In a phase 1 study involving 32 pediatric patients on dialysis, sirolimus was found to be well tolerated with no serious adverse events reported, indicating its safety for use in this population.

Younger patients (ages 5-11) showed significantly higher clearance rates of sirolimus compared to older patients (ages 12-18), suggesting they may need higher maintenance doses to achieve similar drug levels as healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Tejani, A., Alexander, S., Ettenger, R., et al.[2022]

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]

The novel nano-amorphous formulation of sirolimus demonstrated improved pharmacokinetic properties, achieving higher plasma concentrations compared to the standard Rapamune® formulation, suggesting it may be more effective for treating conditions like renal cancer.

This new formulation showed low-to-moderate variability in drug absorption, which could reduce the need for regular therapeutic blood monitoring in kidney transplant patients, making it a potentially safer and more convenient option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers. Basa-Dénes, O., Angi, R., Kárpáti, B., et al.[2020]

Rapamune (Sirolimus) is an important immunosuppressant used in solid organ transplants for various purposes, including induction therapy and managing refractory rejection.

Understanding the pharmacodynamics and side effects of Rapamune is crucial for critical care nurses to enhance patient education and improve outcomes in transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on transplant pharmacology: sirolimus. Hoffmann, RL., Roesch, T.[2021]

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 (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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11064898/

Clinical study reveals the efficacy of sirolimus in treating ... Our study results revealed that sirolimus demonstrated a beneficial effect in a subset of ITP patients, with an overall response rate (ORR) of 55% at 1 month ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2213333X25001192

Effectiveness and safety of sirolimus in the treatment ... Conclusions. Sirolimus is effective and safe for treating venous malformations, especially in patients unresponsive to conventional therapies. Future studies ...

3. ashpublications.org ashpublications.org/blood/article/127/1/17/34867/Sirolimus-is-effective-in-relapsed-refractory

Sirolimus is effective in relapsed/refractory autoimmune ... Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30672136/

Efficacy of systemic sirolimus in the treatment ... - PubMed - NIH Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%).

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02979873

Study Details | NCT02979873 | Sirolimus (Rapamune ) for ... The treatment cyclosporine leads to better blood counts. But when this treatment is stopped, the disease may return in 1 in 3 people. The drug sirolimus may ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/021083s059,021110s076lbl.pdf

RAPAMUNE (sirolimus) Label - accessdata.fda.gov The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended.

7. ema.europa.eu ema.europa.eu/en/documents/product-information/rapamune-epar-product-information_en.pdf

Rapamune, INN-sirolimus - EMA Rapamune is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving a renal transplant.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11325711/

Long-term safety and influence on growth in patients ... Results. Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with ...

9. mayoclinic.org mayoclinic.org/drugs-supplements/sirolimus-oral-route/description/drg-20068199

Sirolimus (oral route) - Side effects & dosage Sirolimus works by preventing the white blood cells from getting rid of the transplanted organ. ... Safety and efficacy have not been established in these age ...

10. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2010/021083s048lbl.pdf

Rapamune (sirolimus) oral solution label - accessdata.fda.gov Data (≥ 12 months post-transplant) presented in the following table show the adverse reactions that occurred in at least one of the Rapamune treatment groups.