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

Trial Summary

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.

What data supports the effectiveness of the drug Sirolimus for blood disorders?

Sirolimus, known for its use in preventing organ rejection in kidney transplants, has shown effectiveness in reducing acute rejection episodes by over 40% when combined with other drugs. Its properties as an immunosuppressant and its ability to inhibit certain cellular pathways suggest potential benefits for treating various conditions, including blood disorders. ^{1 2 3 4 5}

Is Sirolimus generally safe for humans?

Sirolimus, also known as Rapamune, has been shown to have a favorable safety profile in various conditions, including kidney transplants and skin disorders. However, severe adverse events have been reported during its use for vascular anomalies, indicating that while it is generally safe, there can be serious side effects in some cases. ^{1 2 5 6 7}

How is the drug Sirolimus unique for treating blood disorders?

Sirolimus is unique because it works by inhibiting a specific protein called mTOR, which helps control cell growth and immune response. This mechanism is different from other treatments and makes it effective in reducing immune activity, which is beneficial for conditions involving abnormal immune responses. ^{1 2 3 4 8}

What is the purpose of this trial?

To learn about the safety and effects of low-dose sirolimus in participants with RUNX1-FPD.

Research Team

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

References

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

Update on transplant pharmacology: sirolimus. [2021]

2. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

3. England pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. [2019]

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

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. [2019]

5. England 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. [2019]

6. Denmark 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. [2022]

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

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

8. France pubmed.ncbi.nlm.nih.gov

Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers. [2020]