Pre-Transplant Inflammation Treatment for Immune System Disorders

Recruiting at 10 trial locations

Overseen By Roni Tamari, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Uncontrolled infection, Previous allo-HCT, HIV/HTLV, Pregnancy, 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

Compensation: Varies

Number of Visits: 4

39 Participants Needed

Trial Summary

What is the purpose of this trial?

The researchers are doing this study to find out whether emapalumab or a combination of fludarabine and dexamethasone are effective in preparing people with a primary immune regulatory disorder (PIRD) and/or an autoinflammatory condition to receive a stem cell transplant. The researchers will look at how well the study treatments reduce inflammation and aid in the engraftment process (the process of donated stem cells traveling to the bone marrow, where they begin to make new immune cells. "Funding Source - FDA OOPD"

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drugs used in the Pre-Transplant Inflammation Treatment for Immune System Disorders?

Research shows that glucocorticoids like dexamethasone and prednisone are effective anti-inflammatory and immunosuppressive agents, commonly used to manage conditions like rheumatoid arthritis and prevent immune rejection in transplants. These drugs help control inflammation and immune responses, which is crucial in preparing patients for stem cell transplants. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Dexamethasone, a component of the treatment, has been shown to prevent immune rejection in animal studies with minimal adverse effects. Additionally, a fluorinated analog of a related steroid showed increased potency without significant systemic side effects in rats. ^{3 6 7 8 9}

How is the drug Dexamethasone, Emapalumab, Fludarabine unique for treating immune system disorders?

This drug combination is unique because it uses Dexamethasone, a corticosteroid that reduces inflammation, Emapalumab, an antibody that specifically targets and neutralizes a protein involved in immune response, and Fludarabine, which interferes with DNA synthesis in immune cells. This multi-faceted approach aims to effectively manage inflammation and immune activity, potentially offering a more targeted and comprehensive treatment compared to traditional therapies. ^{10 11 12 13 14}

Research Team

Joseph H. Oved, M.D.

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for people with a primary immune regulatory disorder (PIRD) and/or an autoinflammatory condition who need a stem cell transplant. They should have good organ function, be able to handle cytoreduction, and not have had previous transplants. Pregnant or breastfeeding women, HIV/HTLV-positive individuals, and those unwilling to use contraception are excluded.

Inclusion Criteria

I am eligible for a first allo-HCT due to my immune disorder and can tolerate the required treatment.

Exclusion Criteria

Uncontrolled infection at the time of enrollment, Patients who have undergone previous allo-HCT, Patient seropositivity for HIV I/II and/or HTLV I/II, Females who are pregnant or breastfeeding, Patients unwilling to use contraception during the study period, Patient or parent or guardian unable to give informed consent or unable to comply with the treatment protocol including research tests.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Transplant Treatment

Participants receive emapalumab or a combination of fludarabine and dexamethasone to reduce inflammation before stem cell transplant

3 weeks

4 visits (in-person) for emapalumab group, 5 visits (in-person) for fludarabine and dexamethasone group

Stem Cell Transplant

Participants undergo the stem cell transplant procedure

1 week

Follow-up

Participants are monitored for engraftment and overall survival

1 year

Regular visits as per protocol

Long-term Follow-up

Participants are monitored for overall survival and long-term outcomes

5 years

Treatment Details

Interventions

• Dexamethasone
• Emapalumab
• Fludarabine
• Stem Cell Transplant

Trial Overview The study tests if emapalumab alone or in combination with fludarabine and dexamethasone can reduce inflammation effectively before a stem cell transplant in patients with PIRD/autoinflammatory conditions. It aims to improve the engraftment success of the transplant.

Participant Groups

Group I: Group B: Fludarabine and Dexamethasone (for generalized autoinflammation) Experimental Treatment 2 Interventions

Participants in this group will receive fludarabine and dexamethasone for 5 days in a row on Days -22 through -18.

Group II: Group A: Emapalumab (for isolated Interferongamma mediated disease) Experimental Treatment 2 Interventions

Participants in this group will receive emapalumab on Days -22 (22 days before the day of the stem cell transplant), -15, -8, and -1.

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

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Sobi, Inc.

Industry Sponsor

Trials

14

Recruited

1,000+

Findings from Research

In a 22-month study involving 31 patients with essential mixed cryoglobulinemia, both deflazacort (DF) and prednisone (PD) significantly improved symptoms like joint pain and skin purpura within 15 days, with effects maintained throughout the study.

Deflazacort demonstrated more intense and prolonged immunological effects compared to prednisone, with better tolerance and fewer side effects related to glucose and body weight, suggesting it may be a preferable option for treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deflazacort versus Prednisone in the Treatment of Essential Mixed Cryoglobulinemia A Between-Patient Controlled Clinical Study. Vacca, A., Dammacco, F.[2021]

Low doses of prednisone or prednisolone (10 mg daily or 5 mg twice daily) effectively control inflammation and slow bone damage in early polyarticular rheumatoid arthritis, making them original disease-modifying antirheumatic drugs.

These glucocorticoids provide stronger anti-inflammatory effects with fewer side effects compared to NSAIDs or COX-2 inhibitors, and their use can be safely managed with calcium and vitamin D supplementation to minimize the risk of osteopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resolved: Low-dose prednisone is indicated as a standard treatment in patients with rheumatoid arthritis. Conn, DL.[2019]

In a study involving rabbits, fluorometholone was found to be as effective as dexamethasone phosphate and prednisolone acetate in preventing immune rejection of corneal grafts, with only one rejection in each treatment group compared to eight in the control group.

The results suggest that fluorometholone can be a viable alternative to other corticosteroids for preventing corneal graft rejection, as confirmed by histological examination of the grafts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of immune graft rejection after corneal transplantation. Fleming, JC., Reid, FR., Wood, TO.[2021]

High-dose oral prednisone (1mg/kg/day) is the primary treatment for polymyositis/dermatomyositis (PM/DM), and its dosage should be gradually reduced based on how well the patient responds.

For patients who do not respond to prednisone, methotrexate or azathioprine are recommended as first-line immunosuppressive therapies, while TNF-α antagonists are not advised due to safety and efficacy concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of polymyositis and dermatomyositis. Marie, I.[2016]

Glucocorticoids are essential for treating rheumatoid arthritis due to their strong anti-inflammatory and immunosuppressive effects, but they can also cause adverse effects, highlighting the need for safer usage strategies.

The novel delayed-release (DR) prednisone formulation has been shown to improve the benefit-risk ratio of glucocorticoid treatment, and it has recently been approved in the U.S. for various rheumatologic and respiratory conditions, following positive results from the CAPRA studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fresh look at glucocorticoids how to use an old ally more effectively. Buttgereit, F.[2013]

The fluorinated analog of the steroidal antedrug showed twice the potency in reducing inflammation compared to the original compound, indicating enhanced local anti-inflammatory activity.

Importantly, the new fluorinated compound did not increase systemic side effects, which is likely due to its unique chemical structure that limits adverse effects while maintaining efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel fluorinated antiinflammatory steroid with reduced side effects: methyl 9 alpha-fluoroprednisolone-16-carboxylate. McLean, HM., Khalil, MA., Heiman, AS., et al.[2019]

In a 26-week double-blind trial involving 20 patients with Crohn's disease, azathioprine significantly reduced the number of relapses compared to placebo, with only 2 relapses in the azathioprine group versus 7 in the placebo group.

Patients taking azathioprine were able to reduce their steroid dosage more effectively than those on placebo, suggesting that azathioprine may help manage Crohn's disease symptoms while allowing for lower steroid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A controlled trial of azathioprine in Crohn's disease. Rosenberg, JL., Levin, B., Wall, AJ., et al.[2020]

Mofetil microphenolate (MM) is a novel immunosuppressant that shows comparable efficacy to the conventional anti-SLE drug cyclophosphamide, which is known to have poorer tolerance.

The review highlights the potential of MM as a safer alternative for treating systemic lupus erythematosus (SLE), addressing current pharmacotherapy challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New trends in chemotherapy of systemic lupus erythematosus: treatment with mycophenolate mofetil]. Shekshina, SV., Kliukvina, NG., Nasonov, EL., et al.[2016]

Glucocorticoids, particularly high-dose prednisone, are essential for treating pediatric systemic lupus erythematosus (SLE), especially in cases of diffuse proliferative glomerulonephritis (DPGN), where azathioprine is recommended at diagnosis.

Hydroxychloroquine is suggested for routine use in all SLE cases, while methotrexate shows promise with a good safety profile, indicating a need for further research on its efficacy in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of the treatment of childhood SLE. Silverman, ED., Lang, B.[2019]

Immunosuppressive regimens for organ transplants have evolved significantly since the first transplant in 1954, utilizing a combination of drugs with different mechanisms to enhance efficacy while reducing side effects.

The article reviews various classes of immunosuppressants, including glucocorticoids and mTOR inhibitors, highlighting their actions and potential side effects, and discusses future advancements in immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Overview of Transplant Immunosuppression--History, Principles, and Current Practices in Kidney Transplantation. Colaneri, J.[2021]

Immunosuppressive drugs like corticosteroids, azathioprine, cyclophosphamide, cyclosporine, and anti-CD3 monoclonal antibodies work by targeting different aspects of the immune response, with corticosteroids primarily redistributing lymphocytes and reducing inflammation.

These drugs are used effectively in treating conditions such as renal disease, systemic vasculitis, and connective tissue diseases, highlighting their importance in managing autoimmune and inflammatory disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive drugs in clinical medicine. ten Berge, RJ., Schellekens, PT.[2005]

Corticosteroids are commonly used as the first-line treatment for systemic autoimmune diseases, but their long-term use can lead to significant side effects, especially as the dose and duration increase.

To mitigate these side effects, strategies such as combining corticosteroids with immunosuppressants or immunomodulatory agents are recommended, with the choice of treatment tailored to the specific disease and its underlying mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Benefits and risks of treatments used in systemic autoimmune diseases]. Mouthon, L.[2016]

Immunosuppressive drugs have significantly improved the survival rates of patients receiving solid organ transplants by effectively blocking lymphocyte activity, with current treatments primarily based on calcineurin inhibitors like cyclosporine and tacrolimus.

The review highlights the importance of understanding the mechanisms, therapeutic uses, and potential adverse effects of these drugs, while also addressing challenges in managing immunosuppression for transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive agents in transplantation: mechanisms of action and current anti-rejection strategies. Gorantla, VS., Barker, JH., Jones, JW., et al.[2019]

Immunosuppressive agents, while effective, carry significant risks such as increased susceptibility to infections and malignancies, with specific side effects varying by drug class; for example, corticosteroids can lead to osteoporosis and gastrointestinal issues, while cytotoxic agents like azathioprine and methotrexate primarily cause bone marrow suppression.

Cyclosporine is associated with acute and chronic nephrotoxicity, especially when combined with ketoconazole, highlighting the importance of monitoring drug interactions and plasma levels to prevent severe kidney damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunosuppression--a tightrope walk between iatrogenic harm and therapy]. Berchtold, P., Seitz, M.[2013]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Deflazacort versus Prednisone in the Treatment of Essential Mixed Cryoglobulinemia A Between-Patient Controlled Clinical Study. [2021]

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

Resolved: Low-dose prednisone is indicated as a standard treatment in patients with rheumatoid arthritis. [2019]

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

Prevention of immune graft rejection after corneal transplantation. [2021]

4. France pubmed.ncbi.nlm.nih.gov

Therapy of polymyositis and dermatomyositis. [2016]

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

A fresh look at glucocorticoids how to use an old ally more effectively. [2013]

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

Novel fluorinated antiinflammatory steroid with reduced side effects: methyl 9 alpha-fluoroprednisolone-16-carboxylate. [2019]

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

A controlled trial of azathioprine in Crohn's disease. [2020]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[New trends in chemotherapy of systemic lupus erythematosus: treatment with mycophenolate mofetil]. [2016]

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

An overview of the treatment of childhood SLE. [2019]

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

An Overview of Transplant Immunosuppression--History, Principles, and Current Practices in Kidney Transplantation. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Immunosuppressive drugs in clinical medicine. [2005]

12. France pubmed.ncbi.nlm.nih.gov

[Benefits and risks of treatments used in systemic autoimmune diseases]. [2016]

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

Immunosuppressive agents in transplantation: mechanisms of action and current anti-rejection strategies. [2019]

14. Switzerland pubmed.ncbi.nlm.nih.gov

[Immunosuppression--a tightrope walk between iatrogenic harm and therapy]. [2013]