Pre-Transplant Inflammation Treatment for Immune System Disorders
Recruiting in Palo Alto (17 mi)
+9 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Disqualifiers: Uncontrolled infection, Previous allo-HCT, HIV/HTLV, Pregnancy, others
No Placebo Group
Prior Safety Data
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.12345
Is the treatment generally safe for humans?
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.1011121314
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.
Trial 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 (Corticosteroid)
- Emapalumab (Monoclonal Antibodies)
- Fludarabine (Anti-metabolites)
- Stem Cell Transplant (Procedure)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Group I: Group B: Fludarabine and Dexamethasone (for generalized autoinflammation)Experimental Treatment2 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 Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering Bergen (Limited Protocol Activities)Montvale, NJ
University of California, San Francisco (Data collection only)San Francisco, CA
Children's Healthcare of Atlanta (Data Collection Only)Atlanta, GA
Texas Children's Hospital (Data Collection)Houston, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
Sobi, Inc.Industry Sponsor
References
Deflazacort versus Prednisone in the Treatment of Essential Mixed Cryoglobulinemia A Between-Patient Controlled Clinical Study. [2021]Deflazacort (DF) and prednisone (PD) were administered to 31 consecutive symptomatic patients with essential mixed cryoglobulinemia (EMC) in a double-blind randomized study lasting 22 months. 'Loading' doses given for 3 months were tapered to 'control-inducing' and 'minimum effective' doses, according to individual needs. The DF to PD mean dose ratio was 1.32-1.34 at 'loading' doses, 0.81-1.31 at 'control-inducing' doses and 1.14 at 'minimum effective' doses. Both steroids significantly improved arthralgias and purpura within 15 days, and this improvement was maintained over the entire study period. Reduction in the CD3+ and CD4+ cell percentages and the CD4+/CD8+ ratio was found in DF and PD patients within 3 months, whereas these effects persisted after tapering in DF patients only. The cryocrit was consistently decreased in both groups, with a minimum between 8 and 12 months. The ESR and 24-hour urine protein excretion also improved in both groups. Drug tolerance was satisfactory, despite the amount and duration of administered doses. However, glucose tolerance and body weight were mainly affected in PD patients. Assessment of the relative potency DF to PD ratio suggests that, in EMC, the mean standard dose unit of DF 6.6-5.7 mg, is clinically equivalent to PD 5 mg. This study shows that, in EMC, DF is clinically as effective as PD, while its immunological effects are more intense and prolonged.
Resolved: Low-dose prednisone is indicated as a standard treatment in patients with rheumatoid arthritis. [2019]It is known and has been repeatedly demonstrated that low doses of prednisone or prednisolone (10 mg daily or 5 mg bid) will control most of the inflammatory features of early polyarticular rheumatoid arthritis (Table 2). Also, low doses of prednisolone are known to retard the bony damage of rheumatoid arthritis, and thus these are the original disease-modifying antirheumatic drugs. Glucocorticoids are potent antiinflammatory and immunosuppressive agents by virtue of their repression of the genomic expression by transcriptional interference, inhibiting such proinflammatory proteins as COX-2, IL-1, IL-2, IL-6, TNFalpha, and adhesion molecules. Nature has produced an ideal antiinflammatory and immunosuppressive agent, namely glucocorticoids, and it is up to us to use it in appropriate situations (e.g., active early inflammatory polyarticular rheumatoid arthritis) and in low doses, frequently daily divided doses. Low doses of glucocorticoids (prednisone or prednisolone) accomplish everything NSAIDs or COX-2 inhibitors accomplish but with more antiinflammatory effects, fewer side effects, and much less expense. It is certainly possible (but not precisely tested) that low doses of prednisone (prednisolone) enhance the effects of other DMARDs, including anti-TNF agents. The side effects of low-dose glucocorticoids are minimal. By using concomitant calcium and vitamin D and monitoring bone status with DEXA scans, the osteopenia potential of low doses of prednisone will be minimal. The use of low-dose prednisone without NSAIDs will put the patient at very little risk for stomach ulceration and bleeding.
Prevention of immune graft rejection after corneal transplantation. [2021]The effectiveness of fluorometholone was compared to dexamethasone phosphate and prednisolone acetate in preventing the immune corneal graft reaction in rabbits. Clear corneal grafts were obtained. Rejection was induced after skin from the corneal donor animal was grafted subcutaneously in the host animal and the animals were randomized into four treatment groups. Rejection occurred in eight of nine rabbits in the control group; one of eight in the dexamethasone phosphate group; one of eight in the fluorometholone group; and one of ten in the prednisolone acetate group. Histologic examination confirmed the above findings. In this animal study fluorometholone prevented immune graft rejection in a percentage similar to that of prednisolone acetate and dexamethasone phosphate.
Therapy of polymyositis and dermatomyositis. [2016]High-dose oral prednisone (at an initial dose of 1mg/kg/day) is the mainstay of therapy for PM/DM, and should be subsequently tapered slowly based on patients' clinical response. First-line combination of prednisone with intravenous immunoglobulins may be considered in patients with PM/DM-related severe systemic complications, especially in the subgroup exbititing life-threatening esophageal involvement. In patients who failed to respond to prednisone, the first-line immunosuppressive therapy includes methotrexate or azathioprine. Intravenous immunoglobulin therapy should be considered in patients in whom those cytotoxic drugs are contraindicated. In patients who failed to respond to prednisone, methotrexate or azathioprine, there is no general clinical consensus, although the options more often include: combined therapy of methotrexate and azathioprine, mycophenolate mofetil or rituximab. To date, TNF-α antagonists should not be considered in PM/DM patients, as both efficacy and safety concerns have been markedly raised in anti-TNF-α agent-treated PM/DM patients.
A fresh look at glucocorticoids how to use an old ally more effectively. [2013]Glucocorticoids form a mainstay of therapy for rheumatoid arthritis (RA) and other conditions since they exert strong anti-inflammatory, immunosuppressive, and disease-modifying therapeutic effects. However, there is increasing awareness of the potential for these drugs to produce adverse effects. Therefore, improvement of the glucocorticoid benefit-risk ratio represents both a current need and an ongoing challenge. The development of recommendations to implement a more effective and safer use of these important drugs is one useful path to pursue. An additional avenue is the development of innovative glucocorticoids or glucocorticoid receptor ligands. Also, treatment with conventional glucocorticoid preparations currently available to clinicians may be improved. The most advanced development in the latter regard is a novel chronotherapeutic prednisone formulation called delayed- release (DR) or modified-release prednisone. The CAPRA (Circadian Administration of Prednisone in Rheumatoid Arthritis) studies confirmed that optimizing the timing of GC administration improves the benefit-risk ratio of long- term low dose glucocorticoid treatment in patients with rheumatoid arthritis. DR prednisone has been approved in 16 European countries as well as Australia and Israel. Very recently, DR prednisone was also approved in the United States to treat rheumatologic conditions such as RA, polymyalgia rheumatica and psoriatic arthritis, as well as respiratory conditions such as COPD and asthma.
Novel fluorinated antiinflammatory steroid with reduced side effects: methyl 9 alpha-fluoroprednisolone-16-carboxylate. [2019]In an effort to test the hypothesis that 9 alpha-fluorination of a steroidal antedrug would enhance receptor binding affinity and local antiinflammatory activity, without concomitantly increasing adverse systemic effects, a fluorinated analog, 10, of methyl 11 beta, 21-dihydroxy- 3,20-dioxo-1,4-pregnadiene-16 alpha-carboxylate (DP16CM, 1) was synthesized and evaluated. In the acute rat croton oil-induced ear edema bioassay, 10 was found to be twice as potent as 1. This increase in topical potency was consistent with enhanced binding affinity of 10, relative to 1. The IC50 values for displacement of [3H]dexamethasone from glucocorticoid receptors of rat hepatoma tissue culture cells were 0.16, 1.2, and 0.03 microM for 10, 1, and prednisolone, respectively. Following multiple topical ID50 applications of predniosolone, 1, and its new fluorinated analog, 10, in the rat subacute croton oil-induced ear edema bioassay, only prednisolone exhibited significant untoward effects, such as reduction in relative thymus and adrenal weights, plasma corticosterone levels, and normal body weight gain. Thus, while fluroination of 1 enhanced its topical potency, there was not a concomitant increase in untoward systemic effects. This lack of adverse systemic effects is ostensibly due to the presence of the metabolically labile 16-carboxylate ester moiety.
A controlled trial of azathioprine in Crohn's disease. [2020]To determine the efficacy of azathioprine in the treatment of Crohn's disease, a 26-week double-blind trial was performed. 20 patients with Crohn's disease, requiring at least 10 mg of prednisone/day over the 3 months prior to entering the study were randomized into placebo (10 patients) and major criterion of success in the trial. There were 7 relapses in the placebo group (5 patients) and 2 relapses in the azathioprine group (2 patients). Complications including fistulae were not affected by the medications. The mean reduction in steriod dosage in the azathioprine group at the end of the trial (-15.5 mg) was greater than in the placebo group (-6.1 mg). These results suggest that azathioprine may permit reduction or discontinuation of steroids without the worsening of symptoms in some patients who appear to require steroids for control of their symptoms. The clinical features of this "AZA-responsive subgroup" remain to be defined.
[New trends in chemotherapy of systemic lupus erythematosus: treatment with mycophenolate mofetil]. [2016]The review covers current issues of pharmacotherapy of systemic lupus erythematosus (SLE) with a focus on a novel immunodepressant mofetil microphenolate (MM) which is not inferior in efficiency to a conventional anti-SLE drug cyclophosphamide which has a worse tolerance.
An overview of the treatment of childhood SLE. [2019]Current recommendations for the treatment of pediatric SLE are from uncontrolled trials, case reports, retrospective descriptive data or extrapolation from studies in adults. Glucocorticoids are the mainstay of therapy and the doses depend on the disease severity. Diffuse proliferative glomerulonephritis (DPGN) requires high-dose prednisone for prolonged periods of time. We suggest the addition of azathioprine for DPGN at the time of diagnosis of DPGN and reserve cyclophosphamide for refractory cases. While we do not recommend the routine use of cyclophosphamide in this or other forms of lupus nephritis, others advocate the aggressive use of intravenous cyclophosphamide and prednisone. Severe central nervous system disease should be treated with high dose prednisone and immunosuppressive agents are reserved for life-threatening disease or steroid failure or dependency. We suggest the routine use of hydroxychloroquine in all cases of SLE at a dose of 5 mg/kg/day (maximum of 400 mg/day). Methotrexate has been recently used with some success in both children and adults, the safety profile appears to be very good and therefore further studies of this drug are warranted. Collaboration in the development of a limited number of defined treatment protocols and large scale collection of data on a multicenter and multinational basis is needed if we hope to improve the outcome of patients with severe disease.
An Overview of Transplant Immunosuppression--History, Principles, and Current Practices in Kidney Transplantation. [2021]From the historical first transplant in 1954 to the current transplant era, tremendous strides have been made in transplant immunology and immunosuppression. The most common immunosuppressive regimens use a combination of agents with differing modes of action to maximize efficacy and minimize the toxicities associated with each class of agent. The general categories of immunosuppressives are glucocorticoids, antimetabolites, calcineurin inhibitors, anti-lymphocyte antibody therapies (monoclonal and polyclonal), costimulation blockers, and mTOR inhibitors. This article reviews immunosuppressant medications, their actions, and significant side effects; discusses clinical management issues of immunosuppression; and describes future directions for the development of immunosuppressive medications.
Immunosuppressive drugs in clinical medicine. [2005]Immunosuppressive drugs are agents capable of suppressing the development of at least one type of immune response in vivo at doses with minimal side-effects. Some characteristics regarding the mechanism of action of corticosteroids, azathioprine, cyclophosphamide, cyclosporine and monoclonal antibodies anti-CD3 are reviewed. Corticosteroids induce a redistribution of lymphocytes and display an anti-inflammatory effect; the immunosuppressive effect of azathioprine seems to consist mainly of its suppression of the inflammatory response; cyclophosphamide and cyclosporine influence the immune system itself and anti-CD3 monoclonal antibodies suppress cellular immunity fairly specifically. Finally, a brief summary of their use in renal disease, systemic vasculitis and connective tissue diseases is given.
[Benefits and risks of treatments used in systemic autoimmune diseases]. [2016]In most of the cases, corticosteroids represent the first line therapy of systemic autoimmune diseases. However, because of the multiple secondary effects occurring in patients treated with corticosteroids, and because their prevalence is positively correlated with the cumulative dose, daily dose and the age of the patient, a number of strategies have been proposed to reduce the corticosteroid dose including therapeutic association with immunosuppressants and/or immunomodulatory agents. Indications of immunosuppressants vary depending on clinical manifestations and pathogenesis of the disease concerned. Sometimes, immunosuppressants can be prescribed as a first line therapy alone or in association with corticosteroids; in other cases, they can be prescribed as a second line therapy in case of failure of corticosteroid therapy or in case of failure to taper the corticosteroid dose due to disease flare. The choice of the best immunosuppressant depends on the disease and is ideally made on a pathophysiology basis. In this review article, we will review therapeutic indications, modalities of administration, mechanisms of action and adverse events of the main immunosuppressants and/or immunomodulatory agents prescribed in systemic autoimmune diseases.
Immunosuppressive agents in transplantation: mechanisms of action and current anti-rejection strategies. [2019]Over the past century, the concept of interfering with the immune response at various sites by blocking the formation, stimulation, proliferation, and differentiation of lymphocytes has led to relentless development of new immunosuppressive drugs. These agents are associated with reduced risk of short- and long-term toxicity and have dramatically improved allograft and patient survival, especially in recipients of solid organ transplants. Current protocols in such patients are nearly all calcineurin-inhibitor based, using cyclosporine or tacrolimus, as part of dual, triple, or sequential therapy. This review focuses on agents currently in clinical use at transplant centers in United States. The drugs are described in terms of their basic mechanisms of action, therapeutic uses, clinical studies, and adverse effects. In addition, the efficacy and toxicity of a few promising new therapeutic approaches are examined. Finally, important challenges regarding pharmacological immunosuppression as it relates to solid organ and composite tissue allotransplantation are discussed.
[Immunosuppression--a tightrope walk between iatrogenic harm and therapy]. [2013]The therapeutic effect of most immunosuppressive agents is unspecific and therefore often limited by an increased risk of infection by viral, bacterial or fungal organisms as well as by an increased incidence of malignant neoplasms. This short review includes the most commonly used immunosuppressants such as corticosteroids, azathioprine, methotrexate, cyclophosphamide and cyclosporine. The most common risks of long-term corticosteroid treatment are Cushing-like changes, decreased glucose tolerance and the usually benign steroid diabetes. Also clinically important is osteoporosis, since it can be prevented by physical training, calcium supplementation and treatment with vitamin D if necessary. Although there is still no proof of a significantly increased risk of peptic ulcer during steroid therapy, patients may develop gastrointestinal hemorrhage and even perforation without producing pain while being treated with corticosteroids. Mineralocorticoid effects, such as salt and water retention, are seen only with hydrocortisone and prednisone, whereas with synthetic steroids such as dexamethasone, sodium retention is absent despite their strong antiphlogistic activity. The most important side effect of the cytotoxic agents azathioprine, methotrexate and cyclophosphamide is marrow suppression. Due to the high turnover of neutrophils, patients most frequently suffer neutropenia rather than thrombocytopenia or anemia. Neutropenia, as well as impaired humoral and cellular immune mechanisms, are responsible for increased susceptibility to bacterial, viral or parasitic diseases during immunosuppressive therapy. Hepatotoxicity has been reported among patients receiving azathioprine (cholestatic hepatitis) and methotrexate (elevated AST levels and, rarely, liver fibrosis or cirrhosis). Cyclophosphamide causes hemorrhagic cystitis in a substantial proportion of patients, as well as an increased incidence of urothelial neoplasms. Both these side effects may be prevented by Mesna. The most important side effects of cyclosporine are acute and chronic nephrotoxicity usually associated with significantly elevated plasma levels of the drug. It must be borne in mind that severe nephrotoxicity may occur in patients receiving cyclosporine and ketoconazole together, since the latter may inappropriately increase the plasma cyclosporine level.